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78 results on '"Mammi, S."'

1. Persistence of Congenital Mirror Movements after Hemiplegic Stroke

Author

Rocca, M. A., Mezzapesa, D. M., Comola, M., Letizia Leocani, Falini, A., Gatti, R., Mammi, S., Comi, G., Filippi, M., Rocca, Ma, Mezzapesa, Dm, Comola, M, Leocani, ANNUNZIATA MARIA LETIZIA, Falini, Andrea, Gatti, R, Mammi, S, Comi, Giancarlo, and Filippi, Massimo

Subjects
Male, Stroke, Movement Disorders, organic chemicals, fungi, Brain, Humans, Hemiplegia, Aged
Abstract

Summary: We describe a case of hereditary congenital mirror movements (MMs) in a 76-year-old man, who after an ischemic stroke, had persistence of MMs in the paretic hand during voluntary movements of the contralateral arm. By using functional MR imaging to investigate the performance of motor and sensory tasks with the affected and the unaffected hands, we found evidence for increased ipsilateral primary motor cortex activity and reduced transcallosal inhibition. Both these mechanisms are likely to be involved in the genesis of MMs.

Published
2005

4. Characteristic MR lesion pattern and correlation of T1 and T2 lesion volume with neurologic and neuropsychological findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Author

Yousry, T. A., Seelos, K., Mayer, M., Brüning, R., Uttner, I., Dichgans, M., Mammi, S., Straube, A., Mai, N., Massimo Filippi, Yousry, Ta, Seelos, K, Mayer, M, Bruning, R, Uttner, I, Dichgans, M, Mammi, S, Straube, A, Mai, N, and Filippi, Massimo

Subjects
Adult, Male, Neurologic Examination, Brain Diseases, Brain, Cerebral Infarction, Middle Aged, Neuropsychological Tests, Magnetic Resonance Imaging, Cerebrovascular Disorders, Dementia, Multi-Infarct, Humans, Female, Aged
Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an arteriopathy related to a genetic defect of the notch 3 gene on chromosome 19. The purpose of this study was to evaluate lesion distribution and volume using MR imaging and to correlate the lesion volume with the neurologic and neuropsychological findings.Twenty members of two families (14 with CADASIL as determined by linkage analysis, six healthy) were studied with MR imaging. Two observers evaluated the MR findings semiquantitatively and quantitatively. MR results were then correlated with neurologic and neuropsychological findings.A typical pattern of lesion distribution in patients with CADASIL was found: the frontal lobe was the site with the highest lesion load, followed by the temporal lobe and the insula. The total lesion volume on T1-weighted MR images correlated significantly with the degree of disability and the degree of impairment in neuropsychological functions (including attention, memory, and conceptual and visuospatial functions).In CADASIL patients, a common pattern of cerebral lesion distribution is found. The total T1 lesion volume is an important parameter to correlate with disability, as it may prove to be helpful in predicting the natural history of the disease.

Published
1999

18. Kinetic and structural analysis of the early oxidation products of dopamine - Analysis of the interactions with alpha-synuclein

Author

Bisaglia M., Mammi S., and Bubacco L.

Abstract

Oxidative stress appears to be directly involved in the pathogenesis of several neurodegenerative disorders, including Alzheimer and Parkinson diseases. Nigral dopaminergic neurons are particularly exposed to oxidative stress because a pathological accumulation of cytosolic dopamine gives rise to various toxic molecules, including free radicals and reactive quinones. These latter species can react with proteins preventing them from exerting their physiological functions. Among the possible targets of quinones, alpha-synuclein is of primary interest because of its direct involvement in dopamine metabolism. Contrary to the neurotoxic processes, neuromelanin synthesis seems to play a protective role by its ability to sequester a variety of potentially damaging substances. In this study, we carried out a kinetic and structural analysis of the early oxidation products of dopamine. Specifically, considering the potential high toxicity of aminochrome for both cells and mitochondria, we focused our attention on its rearrangement to 5,6-dihydroxyindole. After the spectroscopic characterization of the products derived from the oxidation of dopamine, the structural information obtained was used to analyze the reactivity of quinones toward alpha-synuclein. Our results suggest that indole-5,6-quinone, rather than dopamine-o-quinone or aminochrome, is the reactive species. We propose that the observed reactivity could represent a general reaction pathway whenever cysteinyl residues are absent in proteins or if they are sterically protected.

Published
2007
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21. The Italian multicenter observational study on post-stroke depression (DESTRO)

Author

Paolucci, S. T., Gandolfo, C., Provinciali, L., Torta, R., TOSO AND ON THE BEHALF OF THE DESTRO STUDY GROUP, V., Lagalla, THE DESTRO STUDY GROUP INCLUDES G., Manicone, M. G., Del, M., Gobbo, Paolini, S., Ancona, Bottacchi, E., Corso, G., Aosta, Federico, F., Martino, D, Bari, Salsa, F., Turinese, E., BASSANO DEL GRAPPA VI, Gentile, M., Bogo, S., Belluno, Crisci, M., Sacquegna, T., Bologna, Santamato, V., Pietrarossa, G., Carbonara, Ba, Coppola, G., Toni, V., Trianni, G., Casarano, Le, Pennisi, Giovanni, Bella, Rita, Catania, Ricci, S., Amantini, K., Città, DELLA PIEVE PG, Buzzelli, S., DI FRANCESCO, L., ANGELO PE, CITTÀ S., Antonelli, B, Pelliccia, G., Fermo, Ap, Paolino, E., Iezzi, E., Ferrara, P, Nencini, Sarti, C., Florence, Neri, W., Galletti, G., Forli, Pretta, S., Sette, Genoa, Giaccaglini, E., Sconocchini, C., Iesi, An, Carolei, A., Capannolo, C, Laquila, Musolino, R., Gangemi, S., Vita, G., DI LEO, R., Messina, Comola, M., Mammi, S., Zamperetti, M. A., Defanti, C. A., Milan, DE FALCO, F. A., Santangelo, R., Scarano, V., Naples, M. T, Giordana, Sciolla, R., Orbassano, To, Meneghetti, G., Ottina, M., Padua, Ponari, A., Castiglia, R., Palermo, Mancia, D., Zanferrari, C., Parma, Micieli, G., Zambrelli, E., Pavia, Cardaioli, G., Gallai, V., Perugia, Badino, R., Tassinari, T., PIETRA LIGURE SV, Orlandi, G., Fanucchi, S., Pisa, Ciucci, G., Padoan, G., Ravenna, Gasparini, F., Guidetti, D., Reggio, Emilia, DE ANGELIS, D., Amabile, G. A., Fiermonte, G., Rome, Roberti, C., Foti, A., Roma, Cainelli, L., Chiusole, M., Rovereto, Tn, Pasqualino, S., Intiso, D., GIOVANNI ROTONDO FG, S., Tonizzo, M., Basile, A., VITO AL, S., Tagliamento, Pn, Viviani, P., SANT ARSENIO SA, Stromillo, M. L., Federico, A, Siena, Liboni, W., Pavanelli, E., Bergamasco, B., Cerrato, P., Boghi, A, Cicolin, A., Berra, C., Turin, Zorzon, M., Tommasi, M. A., Chiodo, F., Grandi, Koscica, N., Trieste, Micoli, B., Lorio, R., Venice, Bovi, P., Trabucco, G., Verona, Consoli, D., Galati, F., and Vibo, Valentia

Subjects
Adult, Male, medicine.medical_specialty, Pediatrics, Time Factors, Adolescent, Personality Inventory, Physical examination, Observation, Disability Evaluation, Quality of life, medicine, History of depression, Post-stroke depression, Humans, Psychiatry, Stroke, Depression (differential diagnoses), Aged, Retrospective Studies, Aged, 80 and over, Psychiatric Status Rating Scales, Chi-Square Distribution, medicine.diagnostic_test, Depression, Beck Depression Inventory, Retrospective cohort study, Middle Aged, medicine.disease, Neurology, Italy, Female, Neurology (clinical), Psychology
Abstract

Despite growing information, questions still surround various aspects of post-stroke depression (PSD). The Italian multicenter observational study Destro was designed to help clarify in a large sample the frequency and clinical impact of PSD. A total of 53 centers consecutively admitted 1064 patients with ischemic or hemorrhagic stroke, assessing them periodically in the first 9 months after the event. Patients with depression were followed for two years. Depression was diagnosed on clinical examination, verbal (Beck Depression Inventory) and non-verbal rating systems (Visual Analog Mood Scale), identifying the nosographic condition attributable to the mental state. The patient's clinical history, residual independence, and post-ictus quality of life were also taken into account. PSD was detected in 383 patients (36 %), most of whom had minor depression (80.17 %), with dysthymia, rather than major depression and adaptation disorder. About 80% developed depression within three months of the stroke. Cases with later onset tended to have less severe symptoms. Risk factors were a history of depression, severe disability, previous stroke and female sex, but not the type and site of the vascular lesion. PSD was not correlated with any increase in mortality or cerebrovascular recurrences, but these patients had lower autonomy and quality of life ratings. In conclusion, patients should be close observed in the first few weeks after a stroke in order to check for depression,which is more likely in those with clear risk factors and may spoil their quality of life.

Published
2006

22. The Italian multicenter observational study on post-stroke depression (DESTRO)

Author

Paolucci, S, Gandolfo, C, Provinciali, L, Torta, R, Toso, V, Lagalla, G., Manicone, M. G., Del Gobbo, M., Paolini, S., Bottacchi, E., Corso, G., Federico, F., Martino, D., Salsa, F., Turinese, E., Gentile, M., Bogo, S., Crisci, M., Sacquegna, T., Santamato, V., Pietrarossa, G., Coppola, G., Toni, V., Trianni, G., Pennisi, G., Bella, R., Ricci, S., Amantini, K., Buzzelli, S., Di Francesco, L., Antonelli, B., Pelliccia, G., Paolino, E., Iezzi, E., Nencini, P., Sarti, C., Neri, W., Galletti, G., Pretta, S., Del Sette, M., Giaccaglini, E., Sconocchini, C., Carolei, A., Capannolo, C., Musolino, Rosa Fortunata, Gangemi, S., Vita, Giuseppe, Di Leo, R., Comola, M., Mammi, S., Zamperetti, M. A., Defanti, C. A., De Falco, F. A., Santangelo, R., Scarano, . V., Giordana, M. T., Sciolla, R., Meneghetti, G., Ottina, M., Ponari, A., Castiglia, R., Mancia, D., Zanferrari, C., Micieli, G., Zambrelli, E., Cardaioli, G., Gallai, . V., Badino, R., Tassinari, T., Orlandi, G., Fanucchi, S., Ciucci, G., Padoan, G., Gasparini, F., Guidetti, D., De Angelis, D., Amabile, G. A., Fiermonte, G., Roberti, C., Foti, A., Cainelli, L., Chiusole, M., Pasqualino, S., Intiso, D., Tonizzo, M., Basile, A., Viviani, P., Stromillo, M. L., Federico, A., Liboni, W., Pavanelli, E., Bergamasco, B., Cerrato, P., Boghi, A., Cicolin, A., Berra, C., Zorzon, M., Tommasi, M. A., Chiodo Grandi, F., Koscica, N., Micoli, B., Lorio, R., Bovi, P., Trabucco, G., Consoli, D., Galati, F., Bortolon, F., Morra, M., Crespi, . V., and Braga, M.

Published
2006

24. Garda PDO olive oil: NMR and multivariate statistical analysis

Author

Schievano E, Arosio I, Lava R, Simionato V, Mammi S, and Consonni R

Subjects
PCA, PDO, extra virgin olive oil, NMR
Abstract

Extra virgin olive oils from Garda lake were analysed by means of high resolution H-1 NMR spectroscopy in combination with statistical methods. Selected resonances from acquired spectra were quantified and submitted to PCA analysis (Principal Component Analysis) giving rise to a clear grouping according to their geographical origin, i.e., the Veneto and Lombardia banks of Garda take. Our results indicate the possibility to distinguish extra virgin olive oils of the same Protected Denomination of Origin area - Garda lake - with respect to different microareas.

Published
2006

30. Quantification of the risk of post-stroke depression: the Italian multicenter observational study (DESTRO)

Author

Paolucci, S, Gandolfo, C, Provinciali, L, Torta, R, Sommacal, S, Toso, V, Lagalla, G., Manicone, M. G., Del Gobbo, M., Paolini, S., Bottacchi, E., Corso, G., Federico, F., Martino, D., Salsa, F., Turinese, E., Gentile, M., Bogo, S., Crisci, M., Sacquegna, T., Santamato, V., Pietrarossa, G., Coppola, G., Toni, V., Trianni, G., Pennisi, G., Bella, R., Ricci, S., Amantini, K., Buzzelli, S., Di Francesco, L., Antonelli, B., Pelliccia, G., Paolino, E., Iezzi, E., Nencini, P., Sarti, C., Neri, W., Galletti, G., Pretta, S., Del Sette, M., Giaccaglini, E., Sconocchini, C., Carolei, A., Capannolo, C., Musolino, Rosa Fortunata, Gangemi, S., Vita, Giuseppe, Di Leo, R., Comola, M., Mammi, S., Zamperetti, M. A., Defanti, C. A., Grassivaro, N., Rudelli, G., De Falco, F. A., Santangelo, R., Scarano, V., Giordana, M. T., Sciolla, R., Meneghetti, G., Ottina, M., Ponari, A., Castiglia, R., Mancia, D., Zanferrari, C., Micieli, G., Zambrelli, E., Cardaioli, G., Gallai, V., Badino, R., Tassinari, T., Orlandi, G., Fanucchi, S., Ciucci, G., Padoan, G., Gasparini, F., Guidetti, D., De Angelis, D., Amabile, G. A., Roberti, G. Fiermonte C., Foti, A., Cainelli, L., Chiusole, M., Pasqualino, S., Intiso, D., Tonizzo, M., Basile, A., Viviani, P., Stromillo, M. L., Federico, A., Liboni, W., Pavanelli, E., Bergamasco, B., Cerrato, P., Boghi, A., Cicolin, A., Berra, C., Zorzon, M., Tommasi, M. A., Chiodo Grandi, F., Koscica, N., Micoli, B., Lorio, R., Bovi, P., Trabucco, G., Consoli, D., Galati, F., Bortolon, F., Morra, M., Crespi, V., and Braga, M.

Published
2005

33. Quantification of the risk of post stroke depression : the Italian multicenter observational study DESTRO

Author

Paolucci, S., Gandolfo, C., Provinciali, L., Torta, R., SOMMACAL ON BEHALF OF, S., DESTRO STUDY GROUP AND, Lagalla, V. TOSOPARTICIPANTS IN THE DESTRO STUDY INCLUDE G., M. G, Manicone, DEL GOBBO, M., Paolini, S., Ancona, Bottacchi, E., Corso, G., Aosta, Federico, F., Martino, D., Bari, Salsa, F., Turinese, E, BASSANO DEL GRAPPA VI, Gentile, M., Bogo, S., Belluno, Crisci, M., Sacquegna, T., Bologna, Santamato, V., Pietrarossa, G, Carbonara, Ba, Coppola, G., Toni, V., Trianni, G, Casarano, Le, Pennisi, Giovanni, Bella, Rita, Catania, S, Ricci, Amantini, K., CITTA DELLA PIEVE PG, Buzzelli, S., Di, L., Francesco, ANGELO PE, CITTA S., Antonelli, B., Pelliccia, G., Fermo, Ap, Paolino, E., Iezzi, E., Ferrara, Nencini, P., Sarti, C., Florence, Neri, W., Galletti, G., Forli, Pretta, S., DEL SETTE, M., Genoa, Giaccaglini, E., Sconocchini, C., Iesi, An, Carolei, A., Capannolo, C., Laquila, Musolino, R., Gangemi, S., Vita, G., DI LEO, R., Messina, Comola, M., Mammi, S., Zamperetti, M. A., Defanti, C. A., Grassivaro, N., Rudelli, G., Milan, F. A., De, Falco, Santangelo, R., Scarano, V., Naples, M. T, Giordana, Sciolla, R., Orbassano, To, Meneghetti, G., Ottina, M, Padua, Ponari, A., Castiglia, R., Palermo, Mancia, D., Zanferrari, C, Parma, Micieli, G., Zambrelli, E., Pavia, Cardaioli, G., Gallai, V., Perugia, Badino, R., Tassinari, T., Pietra, Ligure, Orlandi, G., Fanucchi, S., Pisa, Ciucci, G., Padoan, G., Ravenna, Gasparini, F., Guidetti, D., Reggio, Emilia, De, D., Angelis, Amabile, G. A., FIERMONTE ROME, G., Roberti, C., Foti, A, Roma, Cainelli, L., Chiusole, M., Rovereto, Tn, Pasqualino, S, Intiso, D., GIOVANNI ROTONDO FG, S., Tonizzo, M., Basile, A., VITO AL TAGLIAMENTO PN, S., Viviani, P., Santarsenio, Sa, Stromillo, M. L., Federico, A., Siena, W, Liboni, Pavanelli, E., Bergamasco, B., Cerrato, P., Boghi, A., Cicolin, A, Berra, C., Turin, Zorzon, M., Tommasi, M. A., F, Chiodo, Grandi, Koscica, N., Trieste, Micoli, B., Lorio, R., Venice, Bovi, P., Trabucco, G., Verona, Consoli, D., Galati, F., Vibo, Valentia, Bortolon, F., Morra, M., Vicenza, and Crespi, V.

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Multivariate analysis, Adolescent, Sex Factors, Risk Factors, mental disorders, medicine, Humans, Disabled Persons, Risk factor, Stroke, Depression (differential diagnoses), Aged, Aged, 80 and over, Psychiatric Status Rating Scales, Depression, business.industry, Beck Depression Inventory, Middle Aged, medicine.disease, Psychiatry and Mental health, Mood, Italy, Relative risk, Physical therapy, Female, Observational study, business, Follow-Up Studies
Abstract

Objective: The Italian multicenter observational study depression in stroke (DESTRO) aimed to identify risk factors for poststroke depression (PSD) and quantify the likelihood of it arising in various categories of patients. Method: Mood evaluation was performed in 1064 consecutive stroke patients by means of Beck Depression Inventory and Visual Analog Mood Scale. Depressive symptoms were classified using the DSM-IV and revised WHO criteria for depression in the course of a neurological disorder. Results: Poststroke depression was seen in 36% of the survivors, with dysthymia by far the predominant form (80.7%). Female sex, disability, previous cerebrovascular or depressive episodes were significantly associated with an increased risk of depression. Combinations of these factors raised the risk of PSD exponentially, from 24.3 to 89.1%. The site of the stroke did not come into the uni- or multivariate analysis. Conclusion.: At admission, it is possible to predict the likelihood of PSD and quantify the relative risk.

Published
2005

39. Post-stroke depression: research methodology of a large multicentre observational study (DESTRO)

Author

Toso, V, Gandolfo, C, Paolucci, S, Provinciali, L, Torta, R, Grassivaro, N, Lagalla, G., Manicone, M. G., Del Gobbo, M., Paolini, S., Bottacchi, E., Corso, G., Federico, F., Martino, D., Salsa, F., Turinese, E., Gentile, M., Bogo, S., Crisci, M., Sacquegna, T., Santamato, V., Pietrarossa, G., Coppola, G., Pennisi, G. T. r. i. a. n. n. i. G., Bella, R., Ricci, S., Amantini, K., Buzzelli, S., Di Francesco, L., Antonelli, B., Pelliccia, G., Paolino, E., Iezzi, E., Nencini, P., Sarti, C., Neri, W., Galletti, G., Pretta, S., Del Sette, M., Giaccaglini, E., Sconocchini, C., Carolei, A., Capannolo, C., De Falco, F. A., Santangelo, R., Musolino, Rosa Fortunata, Gangemi, S., Vita, Giuseppe, Di Leo, R., Comola, M., Mammi, S., Zamperetti, M. A., Defanti, C. A., Sommacal, S., Rudelli, G., Scarano, V., Giordana, M. T., Sciolla, R., Meneghetti, G., Ottina, M., Ponari, A., Castiglia, R., Mancia, D., Zanferrari, C., Micieli, G., Zambrelli, E., Cardaioli, G., Gallai, V., Badino, R., Tassinari, T., Orlandi, G., Fanucchi, S., Ciucci, G., Padoan, G., Gasparini, F., Guidetti, D., De Angelis, D., Amabile, G. A., Fiermonte, G., Roberti, C., Foti, A., Cainelli, L., Chiusole, M., Viviani, P., Stromillo, M. L., Federico, A., Liboni, W., Pavanelli, E., Bergamasco, B., Cerrato, P., Boghi, A., Cicolin, A., Berra, C., Zorzon, M., Tommasi, M. A., Chiodo Grandi, F., Koscica, N., Micoli, B., Lorio, R., Bovi, P., Trabucco, G., Consoli, D., Galati, F., Bortolon, F., Morra, M., Crespi, V., and Braga, M.

Published
2004

44. Lipopeptaibol metabolites of Tolypocladium Geodes: total synthesis, preferred conformation, and membrane activity

Author

Rainaldi M., Moretto A., Peggion C., Formaggio F., Mammi S., Peggion E., Galvez J.A., Diaz-de-Villegas M.D., Cativiela C., and Toniolo C.

Abstract

We have synthesized by solution methods and characterized the lipopeptaibol metabolite LP237-F8 extracted from the fungus Tolypocladium geodes and five selected analogues with the Etn --> Aib or Etn --> Nva replacement at position 8 and/or a triple Gln --> Glu(OMe) replacement at positions 516, and 9 (Etn = Calpha-ethylnorvaline, Aib = alpha-aminoisobutyric acid, Nva = norvaline). Conformation analysis, performed by FT-IR absorption, NMR, and CD techniques, strongly supports the view that the six terminally blocked decapeptides are highly helical in solution. Helix topology and amphiphilic character are responsible for their remarkable membrane activity. At position 8 the combination of high hydrophobicity and Ca tetrasubstitution, as in the Etn-containing LP237-F8 metabolite, has a positive effect on membrane interaction.

Published
2003

47. Butyltins and Calmodulin: which Interaction?

Author

Cima F., Dominici D., Mammi S., and Ballarin L.

Abstract

Tributyltin (TBT), widely used as an antifouling biocide, is the most abundant pesticide in coastal environments. One of its main toxic effects is immunosuppression in both vertebrates and invertebrates. At sublethal doses of TBT, phagocytes lose their ability to move towards and ingest foreign particles. For short-term cultures of haemocytes (60 min at 25 ° C) of a marine invertebrate, the colonial ascidian Botryllus schlosseri, exposed to 10-5 M TBT, we previously reported dose- and time-dependent impairment of yeast phagocytosis and changes in cell morphology related to cytoskeleton disorganization. These effects are Ca2+-dependent, since inactivation of Ca2+-adenosine triphosphatase and a sustained increase in cytosolic Ca2+ occurred. As TBT can antagonize the effect of chlorpromazine, a specific calmodulin (CaM) inhibitor, and the co- presence of exogenous CaM and TBT in the incubation medium resulted in the absence of effects, we hypothesized an interaction between TBT and CaM. TBT may remove endogenous CaM from cell proteins, thus inactivating them and causing alteration of Ca2+ homeostasis. With the aim of confirming the hypothesis of a direct TBT-CaM interaction, we first studied the effects of co-incubation of TBT with other exogenous proteins on restoring the ability of phagocyte morphology. Although bovine serum albumin was never able to restore cell morphology, the effect of human spectrin was similar to that described for CaM, suggesting a common non-specific mechanism of action based on the interaction of TBT with exposed hydrophobic pouches. We also analysed the conformational changes of pure CaM (10-5 M) in the presence of various concentrations (10-4 to 10-3 M) of TBT and its degradation products, dibutyltin (DBT) and monobutyltin (MBT), by circular dichroism. Results indicate the dose- and time-dependent interaction of TBT with CaM. This interaction is a non-covalent interaction, probably hydrophobic in nature, between the aliphatic chains of TBT and the hydrophobic regions of Ca2+-activated CaM. DBT and MBT turned out to be less active in inducing CaM conformational changes, without any significant differences between the two compounds.

Published
2002

48. Interaction of Bombolitin II with a Membrane-Mimetic Environment: an NMR and Molecular Dynamics Simulation Approach

Author

Monticelli L., Pedini D., Schievano E., Mammi S., and Peggion E.

Abstract

Bombolitins are five natural heptadecapeptides originally isolated from the venom of a bumblebee. They induce lysis of erythrocytes and liposomes and increase the activity of phospholipase A2 (PLA2), that plays an important role in the early steps of the inflammatory process. It has been proposed that PLA2 activation depends on the alteration of the physical state of the membrane. Bombolitin II folds into an alpha-helix in a membrane mimicking environment constituted by SDS micelles [Battistutta et al., Macromol. Chem. Phys., 196 (1995) 2827-2841]. In the present work, the topological orientation of the peptide relative to the micelle was determined, using three spin probes localized in different positions of the water/micelle system. The reduction in intensity of the 1H NMR signals clearly demonstrated that the peptide is located on the surface of the micelle, with its helical axis parallel to the interface. Only a small portion of the helix is exposed to the aqueous environment. Results from NMR experiments were confirmed by molecular dynamics simulations, performed using a two-phase water/decane simulation cell. The timescale for the reorientation of the peptide was between 120 and 450 ps, depending on the starting position of the peptide.

Published
2002

49. Molecular Characterization of a Ligand-Tethered Parathyroid Hormone Receptor

Author

Monticelli L., Mammi S., and Mierke D.F.

Subjects
hormones, hormone substitutes, and hormone antagonists
Abstract

It was recently shown that the covalent tethering of the N-terminus of parathyroid hormone (PTH )to the seventh helical bundle of the G-protein coupled PTH-receptor (PTH1R)leads to autoactivation [Shimizu et al., J.Biol.Chem. 275 (2000) 19456–19460]. Here, we have developed molecular models for the interaction of PTH(1–11)tethered to PTH1R and refined them with molecular dynamics simulations. The starting structure of the ligand/receptor complex is based on experimental data from a series of spectroscopic structural studies of PTH(1–34)and the extracellular domains of PTH1R and intermolecular contact points derived from photoaffinity labeling. The resulting PTH1R/[Arg11]PTH(1–11)complex has the N-terminus of PTH interacting with residues of the third extracellular loop of PTH1R, as a possible mode for receptor activation. The hydrophobic residues leucine-5 and methionine-8,centrally located in the N-terminal alpha-helix of PTH(1–11), are located in deep, well-defined hydrophobic pockets in the central core of the seventh helical bundle, consistent with the requirement of these amino acids for autoactivation. We postulate that the improved signaling properties of [Arg]PTH(1–11)over wild type PTH(1–11)is due to a stable hydrogen bond between Arg11 and E444, at the beginning of TM7. The model provides atomic insight into currently available biochemical data as well as numerous putative ligand/receptor interactions, and thereby may further the rational design of reduced-size PTH agonists at the PTH1 receptor.

Published
2002

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