Search

Your search keyword '"Marco-Marín, Clara [0000-0002-8813-3515]"' showing total 13 results
Start Over Author "Marco-Marín, Clara [0000-0002-8813-3515]"
13 results on '"Marco-Marín, Clara [0000-0002-8813-3515]"'

1. C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein

Author

European Commission, Instituto de Salud Carlos III, Generalitat Valenciana, Marina, Alberto [0000-0002-1334-5273], Llácer, José Luis [0000-0001-5304-1795], Rubio, Vicente [0000-0001-8124-1196], Marco-Marín, Clara [0000-0002-8813-3515], Bravo, Jerónimo [0000-0001-6695-2846], Gargantilla, Marta, Francés-Gómez, Clara, Adhav, Anmol, Forcada-Nadal, Alicia, Martínez-Gualda, Belén, Martí-Marí, Olaia, López-Redondo, Marisa, Melero, Roberto, Marco-Marín, Clara, Gougeard, Nadine, Espinosa, Carolina, Rubio-Del-Campo, Antonio, Ruiz-Partida, Rafael, Hernández-Sierra, María del Pilar, Villamayor-Belinchón, Laura, Bravo, Jerónimo, Llácer, José Luis, Marina, Alberto, Rubio, Vicente, San-Félix, Ana, Geller, Ron, Peréz-Pérez, María-Jesús, European Commission, Instituto de Salud Carlos III, Generalitat Valenciana, Marina, Alberto [0000-0002-1334-5273], Llácer, José Luis [0000-0001-5304-1795], Rubio, Vicente [0000-0001-8124-1196], Marco-Marín, Clara [0000-0002-8813-3515], Bravo, Jerónimo [0000-0001-6695-2846], Gargantilla, Marta, Francés-Gómez, Clara, Adhav, Anmol, Forcada-Nadal, Alicia, Martínez-Gualda, Belén, Martí-Marí, Olaia, López-Redondo, Marisa, Melero, Roberto, Marco-Marín, Clara, Gougeard, Nadine, Espinosa, Carolina, Rubio-Del-Campo, Antonio, Ruiz-Partida, Rafael, Hernández-Sierra, María del Pilar, Villamayor-Belinchón, Laura, Bravo, Jerónimo, Llácer, José Luis, Marina, Alberto, Rubio, Vicente, San-Félix, Ana, Geller, Ron, and Peréz-Pérez, María-Jesús

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, by infecting cells via the interaction of its spike protein (S) with the primary cell receptor angiotensin-converting enzyme (ACE2). To search for inhibitors of this key step in viral infection, we screened an in-house library of multivalent tryptophan derivatives. Using VSV-S pseudoparticles, we identified compound 2 as a potent entry inhibitor lacking cellular toxicity. Chemical optimization of 2 rendered compounds 63 and 65, which also potently inhibited genuine SARS-CoV-2 cell entry. Thermofluor and microscale thermophoresis studies revealed their binding to S and to its isolated receptor binding domain (RBD), interfering with the interaction with ACE2. High-resolution cryoelectron microscopy structure of S, free or bound to 2, shed light on cell entry inhibition mechanisms by these compounds. Overall, this work identifies and characterizes a new class of SARS-CoV-2 entry inhibitors with clear potential for preventing and/or fighting COVID-19.

Published
2023

2. The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: The case of the spike A222V mutation

Author

European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, Comunidad de Madrid, Banco Santander, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Arranz, Rocío [0000-0001-5321-0915], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, The IBV-Covid19-Pipeline, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, Carazo, José M., European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, Comunidad de Madrid, Banco Santander, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Arranz, Rocío [0000-0001-5321-0915], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, The IBV-Covid19-Pipeline, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, and Carazo, José M.

Abstract

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has since reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness.

Published
2022

3. A novel TRMT5 mutation causes a complex inherited neuropathy syndrome: The role of nerve pathology in defining a demyelinating neuropathy

Author

Fundación Isabel Gemio, Generalitat Valenciana, Instituto de Salud Carlos III, European Commission, Marco-Marín, Clara [0000-0002-8813-3515], Argente-Escrig, Herminia, Vílchez, Juan Jesús, Frasquet, Marina, Muelas, Nuria, Azorín, Inmaculada, Vílchez, Roger, Millet-Sancho, Elvira, Pitarch, Inmaculada, Tomás-Vila, Miguel, Vazquez-Costa, Juan F., Mas-Estellés, Fernando, Marco-Marín, Clara, Espinós, Carmen, Serrano-Lorenzo, Pablo, Martín, Miguel A., Lupo, Vincenzo, Sevilla, Teresa, Fundación Isabel Gemio, Generalitat Valenciana, Instituto de Salud Carlos III, European Commission, Marco-Marín, Clara [0000-0002-8813-3515], Argente-Escrig, Herminia, Vílchez, Juan Jesús, Frasquet, Marina, Muelas, Nuria, Azorín, Inmaculada, Vílchez, Roger, Millet-Sancho, Elvira, Pitarch, Inmaculada, Tomás-Vila, Miguel, Vazquez-Costa, Juan F., Mas-Estellés, Fernando, Marco-Marín, Clara, Espinós, Carmen, Serrano-Lorenzo, Pablo, Martín, Miguel A., Lupo, Vincenzo, and Sevilla, Teresa

Abstract

Aims: We aim to present data obtained from three patients belonging to three unrelated families with an infantile onset demyelinating neuropathy associated to somatic and neurodevelopmental delay and to describe the underlying genetic changes. Methods: We performed whole-exome sequencing on genomic DNA from the patients and their parents and reviewed the clinical, muscle and nerve data, the serial neurophysiological studies, brain and muscle MRIs, as well as the respiratory chain complex activity in the muscle of the three index patients. Computer modelling was used to characterise the new missense variant detected. Results: All three patients had a short stature, delayed motor milestone acquisition, intellectual disability and cerebellar abnormalities associated with a severe demyelinating neuropathy, with distinct morphological features. Despite the proliferation of giant mitochondria, the mitochondrial respiratory chain complex activity in skeletal muscle was normal, except in one patient in whom there was a mild decrease in complex I enzyme activity. All three patients carried the same two compound heterozygous variants of the TRMT5 (tRNA Methyltransferase 5) gene, one known pathogenic frameshift mutation [c.312_315del (p.Ile105Serfs*4)] and a second rare missense change [c.665 T > C (p.Ile222Thr)]. TRMT5 is a nuclear-encoded protein involved in the post-transcriptional maturation of mitochondrial tRNA. Computer modelling of the human TRMT5 protein structure suggests that the rare p.Ile222Thr mutation could affect the stability of tRNA binding. Conclusions: Our study expands the phenotype of mitochondrial disorders caused by TRTM5 mutations and defines a new form of recessive demyelinating peripheral neuropathy.

Published
2022

4. Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias

Author

Instituto de Salud Carlos III, European Commission, Fundació La Marató de TV3, Generalitat Valenciana, Ministerio de Educación, Cultura y Deporte (España), Fundació per Amor a L'Art, Marco-Marín, Clara [0000-0002-8813-3515], Martínez-Rubio, Dolores, Hinarejos, Isabel, Sancho, Paula, Gorría-Redondo, Nerea, Bernado-Fonz, Raquel, Tello, Cristina, Marco-Marín, Clara, Martí-Carrera, Itxaso, Martínez-González, María Jesús, García-Ribes, Ainhoa, Baviera-Muñoz, Raquel, Sastre-Bataller, Isabel, Martínez-Torres, Irene, Duat-Rodriguez, Anna, Janeiro, Patricia, Moreno, Esther, Pías-Peleteiro, Leticia, Gordo, Mar, O'Callaghan Ruiz-Gómez, Ángeles, Muñoz, Esteban, Martí, Maria Josep, Sánchez-Monteagudo, Ana, Fuster, Candela, Andrés-Bordería, Amparo, Pons, Roser Maria, Jesús-Maestre, Silvia, Mir, Pablo, Lupo, Vincenzo, Pérez-Dueñas, Belén, Darling, Alejandra, Aguilera-Albesa, Sergio, Espinós, Carmen, Instituto de Salud Carlos III, European Commission, Fundació La Marató de TV3, Generalitat Valenciana, Ministerio de Educación, Cultura y Deporte (España), Fundació per Amor a L'Art, Marco-Marín, Clara [0000-0002-8813-3515], Martínez-Rubio, Dolores, Hinarejos, Isabel, Sancho, Paula, Gorría-Redondo, Nerea, Bernado-Fonz, Raquel, Tello, Cristina, Marco-Marín, Clara, Martí-Carrera, Itxaso, Martínez-González, María Jesús, García-Ribes, Ainhoa, Baviera-Muñoz, Raquel, Sastre-Bataller, Isabel, Martínez-Torres, Irene, Duat-Rodriguez, Anna, Janeiro, Patricia, Moreno, Esther, Pías-Peleteiro, Leticia, Gordo, Mar, O'Callaghan Ruiz-Gómez, Ángeles, Muñoz, Esteban, Martí, Maria Josep, Sánchez-Monteagudo, Ana, Fuster, Candela, Andrés-Bordería, Amparo, Pons, Roser Maria, Jesús-Maestre, Silvia, Mir, Pablo, Lupo, Vincenzo, Pérez-Dueñas, Belén, Darling, Alejandra, Aguilera-Albesa, Sergio, and Espinós, Carmen

Abstract

Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype.

Published
2022

5. Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3

Author

Instituto de Salud Carlos III, European Commission, Ministerio de Economía y Competitividad (España), Fundació La Marató de TV3, Generalitat Valenciana, Ministerio de Ciencia e Innovación (España), Marco-Marín, Clara [0000-0002-8813-3515], Martínez-Rubio, Dolores, Rodríguez-Prieto, Ángela, Sancho, Paula, Navarro-González, Carmen, Gorría-Redondo, Nerea, Miquel-Leal, Javier, Marco-Marín, Clara, Jenkins, Alison, Soriano-Navarro, Mario, Hernández, Alberto, Pérez-Dueñas, Belén, Fazzari, Pietro, Aguilera-Albesa, Sergio, Espinós, Carmen, Instituto de Salud Carlos III, European Commission, Ministerio de Economía y Competitividad (España), Fundació La Marató de TV3, Generalitat Valenciana, Ministerio de Ciencia e Innovación (España), Marco-Marín, Clara [0000-0002-8813-3515], Martínez-Rubio, Dolores, Rodríguez-Prieto, Ángela, Sancho, Paula, Navarro-González, Carmen, Gorría-Redondo, Nerea, Miquel-Leal, Javier, Marco-Marín, Clara, Jenkins, Alison, Soriano-Navarro, Mario, Hernández, Alberto, Pérez-Dueñas, Belén, Fazzari, Pietro, Aguilera-Albesa, Sergio, and Espinós, Carmen

Abstract

Peroxiredoxin 3 (PRDX3) encodes a mitochondrial antioxidant protein, which is essential for the control of reactive oxygen species homeostasis. So far, PRDX3 mutations are involved in mild-to-moderate progressive juvenile onset cerebellar ataxia. We aimed to unravel the molecular bases underlying the disease in an infant suffering from cerebellar ataxia that started at 19 months old and presented severe cerebellar atrophy and peripheral neuropathy early in the course of disease. By whole exome sequencing, we identified a novel homozygous mutation, PRDX3 p.D163E, which impaired the mitochondrial ROS defense system. In mouse primary cortical neurons, the exogenous expression of PRDX3 p.D163E was reduced and triggered alterations in neurite morphology and in mitochondria. Mitochondrial computational parameters showed that p.D163E led to serious mitochondrial alterations. In transfected HeLa cells expressing the mutation, mitochondria accumulation was detected by correlative light electron microscopy. Mitochondrial morphology showed severe changes, including extremely damaged outer and inner membranes with a notable cristae disorganization. Moreover, spherical structures compatible with lipid droplets were identified, which can be associated with a generalized response to stress and can be involved in the removal of unfolded proteins. In the patient's fibroblasts, PRDX3 expression was nearly absent. The biochemical analysis suggested that the mutation p.D163E would result in an unstable structure tending to form aggregates that trigger unfolded protein responses via mitochondria and endoplasmic reticulum. Altogether, our findings broaden the clinical spectrum of the recently described PRDX3-associated neurodegeneration and provide new insight into the pathological mechanisms underlying this new form of cerebellar ataxia.

Published
2022

6. The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: the case of the spike A222V mutation

Author

European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Comunidad de Madrid, European Research Council, Instituto de Salud Carlos III, Banco Santander, Generalitat Valenciana, Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, López-Redondo, Marisa, Francés-Gómez, Clara, Ruiz-Rodríguez, Paula, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, Carazo, José M., European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Comunidad de Madrid, European Research Council, Instituto de Salud Carlos III, Banco Santander, Generalitat Valenciana, Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, López-Redondo, Marisa, Francés-Gómez, Clara, Ruiz-Rodríguez, Paula, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, and Carazo, José M.

Abstract

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has now reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness.

Published
2021

7. The PII-NAGK-PipX-NtcA Regulatory Axis of Cyanobacteria: A Tale of Changing Partners, Allosteric Effectors and Non-covalent Interactions

Author

Ministerio de Economía y Competitividad (España), Llácer, José Luis [0000-0001-5304-1795], Rubio, Vicente [0000-0001-8124-1196], Marco-Marín, Clara [0000-0002-8813-3515], Forcada-Nadal, Alicia [0000-0003-0179-4044], Forcada-Nadal, Alicia, Llácer, José Luis, Contreras, Asunción, Marco-Marín, Clara, Rubio, Vicente, Ministerio de Economía y Competitividad (España), Llácer, José Luis [0000-0001-5304-1795], Rubio, Vicente [0000-0001-8124-1196], Marco-Marín, Clara [0000-0002-8813-3515], Forcada-Nadal, Alicia [0000-0003-0179-4044], Forcada-Nadal, Alicia, Llácer, José Luis, Contreras, Asunción, Marco-Marín, Clara, and Rubio, Vicente

Abstract

PII, a homotrimeric very ancient and highly widespread (bacteria, archaea, plants) key sensor-transducer protein, conveys signals of abundance or poorness of carbon, energy and usable nitrogen, converting these signals into changes in the activities of channels, enzymes, or of gene expression. PII sensing is mediated by the PII allosteric effectors ATP, ADP (and, in some organisms, AMP), 2-oxoglutarate (2OG; it reflects carbon abundance and nitrogen scarcity) and, in many plants, L-glutamine. Cyanobacteria have been crucial for clarification of the structural bases of PII function and regulation. They are the subject of this review because the information gathered on them provides an overall structure-based view of a PII regulatory network. Studies on these organisms yielded a first structure of a PII complex with an enzyme, (N-acetyl-Lglutamate kinase, NAGK), deciphering how PII can cause enzyme activation, and how it promotes nitrogen stockpiling as arginine in cyanobacteria and plants. They have also revealed the first clear-cut mechanism by which PII can control gene expression. A small adaptor protein, PipX, is sequestered by PII when nitrogen is abundant and is released when is scarce, swapping partner by binding to the 2OG-activated transcriptional regulator NtcA, co-activating it. The structures of PII-NAGK, PII-PipX, PipX alone, of NtcA in inactive and 2OG-activated forms and as NtcA-2OG-PipX complex, explain structurally PII regulatory functions and reveal the changing shapes and interactions of the T-loops of PII depending on the partner and on the allosteric effectors bound to PII. Cyanobacterial studies have also revealed that in the PII-PipX complex PipX binds an additional transcriptional factor, PlmA, thus possibly expanding PipX roles beyond NtcA-dependency. Further exploration of these roles has revealed a functional interaction of PipX with PipY, a pyridoxal-phosphate (PLP) protein involved in PLP homeostasis whose mutations in the human ortholog

Published
2018

8. A newly distal hereditary motor neuropathy caused by a rare AIFM1 mutation

Author

Instituto de Salud Carlos III, Ministerio de Educación, Cultura y Deporte (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), Marco-Marín, Clara [0000-0002-8813-3515], Sancho, Paula, Sánchez-Monteagudo, Ana, Collado, Antonio, Marco-Marín, Clara, Domínguez-Gonzalez, Cristina, Camacho, Ana, Knecht, Erwin, Espinós, Carmen, Lupo, Vincenzo, Instituto de Salud Carlos III, Ministerio de Educación, Cultura y Deporte (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), Marco-Marín, Clara [0000-0002-8813-3515], Sancho, Paula, Sánchez-Monteagudo, Ana, Collado, Antonio, Marco-Marín, Clara, Domínguez-Gonzalez, Cristina, Camacho, Ana, Knecht, Erwin, Espinós, Carmen, and Lupo, Vincenzo

Abstract

In two siblings, who suffer from an early childhood-onset axonal polyneuropathy with exclusive involvement of motor fibers, the c.629T>C (p.F210S) mutation was identified in the X-linked AIFM1 gene, which encodes for the apoptosis-inducing factor (AIF). The mutation was predicted as deleterious, according to in silico analysis. A decreased expression of the AIF protein, altered cellular morphology, and a fragmented mitochondrial network were observed in the proband's fibroblasts. This new form of motor neuropathy expands the phenotypic spectrum of AIFM1 mutations and therefore, the AIFM1 gene should be considered in the diagnosis of hereditary motor neuropathies.

Published
2017

9. A novel TRMT5 mutation causes a complex inherited neuropathy syndrome: The role of nerve pathology in defining a demyelinating neuropathy

Author

Herminia Argente‐Escrig, Juan J. Vílchez, Marina Frasquet, Nuria Muelas, Inmaculada Azorín, Roger Vílchez, Elvira Millet‐Sancho, Inmaculada Pitarch, Miguel Tomás‐Vila, Juan F. Vázquez‐Costa, Fernando Mas‐Estellés, Clara Marco‐Marín, Carmen Espinós, Pablo Serrano‐Lorenzo, Miguel A. Martin, Vincenzo Lupo, Teresa Sevilla, Fundación Isabel Gemio, Generalitat Valenciana, Instituto de Salud Carlos III, European Commission, Marco-Marín, Clara [0000-0002-8813-3515], and Marco-Marín, Clara

Subjects
Mitochondrial disorders, tRNA Methyltransferases, Mitochondrial Diseases, Histology, Inherited neuropathy, Mitochondrial neuropathies, Peripheral Nervous System Diseases, Syndrome, Pathology and Forensic Medicine, Phenotype, mitochondrial disorders, RNA, Transfer, Neurology, inherited neuropathy, TRMT5, Physiology (medical), Mutation, Humans, Neurology (clinical), mitochondrial neuropathies
Abstract

14 páginas, 4 figuras, 3 tablas, Aims: We aim to present data obtained from three patients belonging to three unrelated families with an infantile onset demyelinating neuropathy associated to somatic and neurodevelopmental delay and to describe the underlying genetic changes. Methods: We performed whole-exome sequencing on genomic DNA from the patients and their parents and reviewed the clinical, muscle and nerve data, the serial neurophysiological studies, brain and muscle MRIs, as well as the respiratory chain complex activity in the muscle of the three index patients. Computer modelling was used to characterise the new missense variant detected. Results: All three patients had a short stature, delayed motor milestone acquisition, intellectual disability and cerebellar abnormalities associated with a severe demyelinating neuropathy, with distinct morphological features. Despite the proliferation of giant mitochondria, the mitochondrial respiratory chain complex activity in skeletal muscle was normal, except in one patient in whom there was a mild decrease in complex I enzyme activity. All three patients carried the same two compound heterozygous variants of the TRMT5 (tRNA Methyltransferase 5) gene, one known pathogenic frameshift mutation [c.312_315del (p.Ile105Serfs*4)] and a second rare missense change [c.665 T > C (p.Ile222Thr)]. TRMT5 is a nuclear-encoded protein involved in the post-transcriptional maturation of mitochondrial tRNA. Computer modelling of the human TRMT5 protein structure suggests that the rare p.Ile222Thr mutation could affect the stability of tRNA binding. Conclusions: Our study expands the phenotype of mitochondrial disorders caused by TRTM5 mutations and defines a new form of recessive demyelinating peripheral neuropathy., Fundación Isabel Gemio; Generalitat Valenciana, Grant/Award Number:PROMETEO/2018/13; Fondo Europeo deDesarrollo Regional (FEDER); Instituto deSalud Carlos III, Grant/Award Numbers:PI19/01178, PI18/01374, PI16/00403

Published
2022

10. Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias

Author

Dolores Martínez-Rubio, Isabel Hinarejos, Paula Sancho, Nerea Gorría-Redondo, Raquel Bernadó-Fonz, Cristina Tello, Clara Marco-Marín, Itxaso Martí-Carrera, María Jesús Martínez-González, Ainhoa García-Ribes, Raquel Baviera-Muñoz, Isabel Sastre-Bataller, Irene Martínez-Torres, Anna Duat-Rodríguez, Patrícia Janeiro, Esther Moreno, Leticia Pías-Peleteiro, Mar O’Callaghan Gordo, Ángeles Ruiz-Gómez, Esteban Muñoz, Maria Josep Martí, Ana Sánchez-Monteagudo, Candela Fuster, Amparo Andrés-Bordería, Roser Maria Pons, Silvia Jesús-Maestre, Pablo Mir, Vincenzo Lupo, Belén Pérez-Dueñas, Alejandra Darling, Sergio Aguilera-Albesa, Carmen Espinós, Institut Català de la Salut, [Martínez-Rubio D, Hinarejos I] Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain. Joint Unit CIPF-IIS La Fe Rare Diseases, Valencia, Spain. [Sancho P, Tello C] Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain. [Gorría-Redondo N, Bernadó-Fonz R] Paediatric Neurology Unit, Department of Paediatrics, Hospital Universitario de Navarra, Navarrabiomed, Pamplona, Spain. [Pérez-Dueñas B] Servei de Neurologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Instituto de Salud Carlos III, European Commission, Fundació La Marató de TV3, Generalitat Valenciana, Ministerio de Educación, Cultura y Deporte (España), Fundació per Amor a L'Art, Marco-Marín, Clara [0000-0002-8813-3515], and Marco-Marín, Clara

Subjects
Iron, Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES], Kinesins, Catalysis, Atàxia - Aspectes genètics, Inorganic Chemistry, cerebellar atrophy, gene panel, Other subheadings::Other subheadings::/genetics [Other subheadings], Humans, movement disorders, ataxia, neurodegeneration with brain iron accumulation (NBIA), exome sequencing, Physical and Theoretical Chemistry, Molecular Biology, fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS], Spectroscopy, Movement Disorders, Otros calificadores::Otros calificadores::/genética [Otros calificadores], Organic Chemistry, Brain, Neurodegenerative Diseases, General Medicine, Computer Science Applications, Fenotip, Phosphotransferases (Alcohol Group Acceptor), Anomalies cromosòmiques, Phenotype, enfermedades del sistema nervioso::manifestaciones neurológicas::discinesias::ataxia [ENFERMEDADES], Mutation, Genetic Phenomena::Phenotype [PHENOMENA AND PROCESSES], Ataxia, fenómenos genéticos::fenotipo [FENÓMENOS Y PROCESOS], Nervous System Diseases::Neurologic Manifestations::Dyskinesias::Ataxia [DISEASES]
Abstract

26 páginas, 4 figuras, 3 tablas, Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype., This work was supported by the Instituto de Salud Carlos III (ISCIII)—Subdirección General de Evaluación y Fomento de la Investigación within the framework of the National R + D+I Plan co-funded with European Regional Development Funds (ERDF) [Grants PI18/00147 and PI21/00103 to CE]; the Fundació La Marató TV3 [Grants 20143130 and 20143131 to BPD and CE]; and by the Generalitat Valenciana [Grant PROMETEO/2018/135 to CE]. Part of the equipment employed in this work was funded by Generalitat Valenciana and co-financed with ERDF (OP ERDF of Comunitat Valenciana 2014–2020). PS had an FPU-PhD fellowship funded by the Spanish Ministry of Education, Culture and Sport [FPU15/00964]. IH has a PFIS-PhD fellowship [FI19/00072]. ASM has a contract funded by the Spanish Foundation Per Amor a l’Art (FPAA)

Published
2022

11. A newly distal hereditary motor neuropathy caused by a rare AIFM1 mutation

Author

Erwin Knecht, Antonio Collado, Vincenzo Lupo, Cristina Domínguez-González, Ana Sánchez-Monteagudo, Paula Sancho, Carmen Espinós, Clara Marco-Marín, Ana Camacho, Instituto de Salud Carlos III, Ministerio de Educación, Cultura y Deporte (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), Marco-Marín, Clara, and Marco-Marín, Clara [0000-0002-8813-3515]

Subjects
Male, 0301 basic medicine, Proband, Gene panel, AIFM1, In silico, Biology, medicine.disease_cause, Muscular Atrophy, Spinal, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Genes, X-Linked, Genetics, medicine, Humans, Gene, health care economics and organizations, Genetics (clinical), Mutation, Infant, Proteins, Phenotype, Human genetics, Pedigree, Mitochondrial disorder, Apoptosis inducing factor, 030104 developmental biology, Cancer research, Apoptosis-inducing factor, Female, Inherited peripheral neuropathies, 030217 neurology & neurosurgery
Abstract

6 Páges, 1 Figure, 1 Table. The online version of this article (https://doi.org/10.1007/s10048-017-0524-6) contains supplementary material, which is available to authorized users., In two siblings, who suffer from an early childhood-onset axonal polyneuropathy with exclusive involvement of motor fibers, the c.629T>C (p.F210S) mutation was identified in the X-linked AIFM1 gene, which encodes for the apoptosis-inducing factor (AIF). The mutation was predicted as deleterious, according to in silico analysis. A decreased expression of the AIF protein, altered cellular morphology, and a fragmented mitochondrial network were observed in the proband's fibroblasts. This new form of motor neuropathy expands the phenotypic spectrum of AIFM1 mutations and therefore, the AIFM1 gene should be considered in the diagnosis of hereditary motor neuropathies., This project was funded by the Instituto de Salud Carlos III (ISCIII)–FEDER (grant nos. PI12/00453 and PI15/00187). P.S. has a FPU grant funded by the Ministerio de Educación, Cultura y Deporte (grant no. FPU15/00964). A.S.M. has a grant funded by the Fundació per amor a l’art (FPAA). C.E. has a BMiguel Servet^ contract funded by the ISCIII and Centro de Investigación Príncipe Felipe (CIPF) (grant no. CPII14/00002). The Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) is an initiative from the ISCIII.

Published
2017

12. The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: the case of the spike A222V mutation

Author

Ginex, Tiziana, Marco-Marín, Clara, Wieczór, Miłosz, Mata, Carlos P., Krieger, James, López-Redondo, Maria Luisa, Francés-Gómez, Clara, Ruiz-Rodriguez, Paula, Melero, Roberto, Sánchez-Sorzano, Carlos Óscar, Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Bravo, Jeronimo, Rubio, Vicente, Marina, Alberto, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscolla, Mireia, Orozco, Modesto, Llácer, José Luis, Carazo, José-Maria, European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Comunidad de Madrid, European Research Council, Instituto de Salud Carlos III, Banco Santander, Generalitat Valenciana, Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, López-Redondo, Marisa, Francés-Gómez, Clara, Ruiz-Rodríguez, Paula, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, and Carazo, José M.

Subjects
0303 health sciences, 03 medical and health sciences, 010402 general chemistry, 01 natural sciences, 3. Good health, 030304 developmental biology, 0104 chemical sciences
Abstract

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has now reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness., This research work was supported by the European Commission–NextGenerationEU through the CSIC Global Health Platform. Additionally, authors would like to acknowledge economic support from the Spanish Ministry of Science and Innovation through Grants: PID2019-104757RB-I00 funded by MCIN/AEI/ 10.13039/501100011033, RTI2018-094399-A-I00, and “ERDF A way of making Europe”, by the “European Union”, Grant SEV 2017-0712 funded by MCIN/AEI /10.13039/501100011033, the “Comunidad Autónoma de Madrid" through Grant: S2017/BMD3817, and the European Union (EU) and Horizon 2020 through grants: Marie-Curie Fellowship EnLaCES (MSCA IF 2020, Proposal: 101024130) (to JK), HighResCells (ERC - 2018 - SyG, Proposal: 810057), and iNEXT-Discovery (Proposal: 871037). AM, VR, JB and JLL are funded by CIBERER-ISCIII (proposal: COV20/00437), Fondo Supera COVID-19 (proposal: CSICCOVID19-082), Banco Santander (Proposal: BlockAce), and CSIC PTI Salud Global (Proposal: 202080E110). VR is funded by the Spanish Ministry of Science and Innovation through Grant PID2020-120322RB-C21. IC is funded by project PID2019-104477RB-100, Fondo COVID COV20/00140 and ERC CoG 101001038. MC is funded by the RyC program from the Spanish Ministry of Science and Innovation, the Generalitat Valenciana (SEJI/2019/011).

Full Text
View/download PDF

13. The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: The case of the spike A222V mutation

Author

Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, The IBV-Covid19-Pipeline, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, Carazo, José M., European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, Comunidad de Madrid, Banco Santander, Instituto de Salud Carlos III, Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Arranz, Rocío [0000-0001-5321-0915], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, and Carazo, José M.

Subjects
Vaccines, SARS-CoV-2, Mutació (Biologia), Immunology, COVID-19, Peptidyl-Dipeptidase A, Mutation (Biology), Vacunes, Infections, Microbiology, Infeccions, Virology, Mutation, Spike Glycoprotein, Coronavirus, Genetics, Humans, Receptors, Virus, Parasitology, Angiotensin-Converting Enzyme 2, Genetic Background, Molecular Biology, Protein Binding
Abstract

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has since reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness., In this research work, PRR and TG were supported by salaries from the European Commission–NextGenerationEU through the CSIC Global Health Platform established by EU Council Regulation 2020/2094. The authors would like to acknowledge economic support from: (a) the Spanish Ministry of Science and Innovation through grants: SEV-2017-0712 funded by MCIN/AEI/10.13039/501100011033 (CPM, JK, RM, COSS, MM, RA, JMC); 116880GB-I00 (JLL) and 120322RB-C21 (VR) funded within PID 2020; PID2019-104757RB-I00 funded by MCIN/AEI/10.13039/501100011033/ and “ERDF A way of making Europe”, by the “European Union” (JMC, COSS, RM, MM, CPM) and 104477RB-100 (IC) funded within PID 2019; RYC-2015-18213 (salary of MC) and RYC-2015-17517 (salary of RG) funded by the Ramon y Cajal fellowship program; RTI2018-094399-A-I00 (JMC, COSS, RM, CPM, MC) funded within the Retos Investigación program; the CRIOMECORR project funded as ESFRI-2019-01-CSIC-16; (b) the Horizon 2020 program through Marie Skłodowska-Curie Individual Fellowships EnLaCES (Proposal 101024130, salary of JK) and EPIDNA (Grant ID: 894498, salary of MW); (c) the European Research Council (ERC) through grants: ERC-2018-SyG-810057 HighResCells funded within the EXCELLENT SCIENCE program (JMC, MM, COSS, salary of RM), Grant 871037 iNEXT DISCOVERY (JMC, MM, COSS) and grant CoG-101001038 funded within the Consolidator Grants program (IC); (d) Generalitat Valenciana through grants: SEJI/2019/011 (MC) and SEJI/2019/030 (JLL); (e) Comunidad de Madrid through grant: S2017/BMD-3817 (JMC); (f) Santander Bank through grant: CSIC-COVID19-082 (AM, VR, JB, JLL, RG) funded through the Fondo Supera Covid-19; (g) Instituto de Salud Carlos III through grants: COV20/00437 (AM, VR, JB, JLL) and COV20/00140 (IC), both funded through the Fondos Covid-19 initiative; (h) Spanish National Research Council through grant: 202080E110 funded within the PTI Salud Global initiative (AM, VR, JB, JLL, RG).

Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results