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Start Over Author "Dina Stockwell" Journal nature communications
3 results on '"Dina Stockwell"'

1. Cryo-EM structure of the extracellular domain of murine Thrombopoietin Receptor in complex with Thrombopoietin

Author

Kaiseal T. G. Sarson-Lawrence, Joshua M. Hardy, Josephine Iaria, Dina Stockwell, Kira Behrens, Tamanna Saiyed, Cyrus Tan, Leila Jebeli, Nichollas E. Scott, Toby A. Dite, Nicos A. Nicola, Andrew P. Leis, Jeffrey J. Babon, and Nadia J. Kershaw

Subjects
Science
Abstract

Abstract Thrombopoietin (Tpo) is the primary regulator of megakaryocyte and platelet numbers and is required for haematopoetic stem cell maintenance. Tpo functions by binding its receptor (TpoR, a homodimeric Class I cytokine receptor) and initiating cell proliferation or differentiation. Here we characterise the murine Tpo:TpoR signalling complex biochemically and structurally, using cryo-electron microscopy. Tpo uses opposing surfaces to recruit two copies of receptor, forming a 1:2 complex. Although it binds to the same, membrane-distal site on both receptor chains, it does so with significantly different affinities and its highly glycosylated C-terminal domain is not required. In one receptor chain, a large insertion, unique to TpoR, forms a partially structured loop that contacts cytokine. Tpo binding induces the juxtaposition of the two receptor chains adjacent to the cell membrane. The therapeutic agent romiplostim also targets the cytokine-binding site and the characterisation presented here supports the future development of improved TpoR agonists.

Published
2024
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2. A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction

Author

Joanne M. Hildebrand, Maria Kauppi, Ian J. Majewski, Zikou Liu, Allison J. Cox, Sanae Miyake, Emma J. Petrie, Michael A. Silk, Zhixiu Li, Maria C. Tanzer, Gabriela Brumatti, Samuel N. Young, Cathrine Hall, Sarah E. Garnish, Jason Corbin, Michael D. Stutz, Ladina Di Rago, Pradnya Gangatirkar, Emma C. Josefsson, Kristin Rigbye, Holly Anderton, James A. Rickard, Anne Tripaydonis, Julie Sheridan, Thomas S. Scerri, Victoria E. Jackson, Peter E. Czabotar, Jian-Guo Zhang, Leila Varghese, Cody C. Allison, Marc Pellegrini, Gillian M. Tannahill, Esme C. Hatchell, Tracy A. Willson, Dina Stockwell, Carolyn A. de Graaf, Janelle Collinge, Adrienne Hilton, Natasha Silke, Sukhdeep K. Spall, Diep Chau, Vicki Athanasopoulos, Donald Metcalf, Ronald M. Laxer, Alexander G. Bassuk, Benjamin W. Darbro, Maria A. Fiatarone Singh, Nicole Vlahovich, David Hughes, Maria Kozlovskaia, David B. Ascher, Klaus Warnatz, Nils Venhoff, Jens Thiel, Christine Biben, Stefan Blum, John Reveille, Michael S. Hildebrand, Carola G. Vinuesa, Pamela McCombe, Matthew A. Brown, Benjamin T. Kile, Catriona McLean, Melanie Bahlo, Seth L. Masters, Hiroyasu Nakano, Polly J. Ferguson, James M. Murphy, Warren S. Alexander, and John Silke

Subjects
Science
Abstract

Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region.

Published
2020
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3. A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction

Author

Cody C. Allison, Benjamin T. Kile, Esme C. Hatchell, Maria Kozlovskaia, Catriona McLean, Pradnya Gangatirkar, Gabriela Brumatti, Marc Pellegrini, Pamela A. McCombe, Julie Sheridan, Donald Metcalf, Klaus Warnatz, Natasha Silke, Maria C. Tanzer, Janelle E. Collinge, Seth L. Masters, Victoria E. Jackson, Jason Corbin, David B. Ascher, Dina Stockwell, Nicole Vlahovich, Zhixiu Li, James M. Murphy, Carola G. Vinuesa, Maria Kauppi, Ronald M. Laxer, John Reveille, Adrienne A. Hilton, John Silke, Ian J. Majewski, David Hughes, Gillian M. Tannahill, Melanie Bahlo, Christine Biben, Michael A. Silk, Maria A. Fiatarone Singh, Cathrine Hall, Peter E. Czabotar, Jian-Guo Zhang, Polly J. Ferguson, Sukhdeep K Spall, Carolyn A. de Graaf, Michael D. Stutz, Nils Venhoff, Alexander G. Bassuk, Zikou Liu, Holly Anderton, Michael S. Hildebrand, Tracy A. Willson, James A Rickard, Hiroyasu Nakano, Vicki Athanasopoulos, Matthew A. Brown, Samuel N. Young, Jens Thiel, Emma J. Petrie, Diep Chau, Sarah E Garnish, Sanae Miyake, Anne Tripaydonis, Warren S. Alexander, Allison Cox, Stefan Blum, Joanne M Hildebrand, Thomas S. Scerri, Kristin A Rigbye, Leila N. Varghese, Benjamin W. Darbro, Emma C. Josefsson, and Ladina Di Rago

Subjects
0301 basic medicine, Programmed cell death, Necroptosis, Hematopoietic System, Science, Mutation, Missense, General Physics and Astronomy, Biology, Inflammatory diseases, Compound heterozygosity, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, Missense mutation, Animals, Humans, lcsh:Science, Inflammation, Mutation, Multidisciplinary, Haematopoietic stem cells, Chronic recurrent multifocal osteomyelitis, Hereditary Autoinflammatory Diseases, Heterozygote advantage, Osteomyelitis, General Chemistry, medicine.disease, Hematopoietic Stem Cells, Phenotype, 030104 developmental biology, Animals, Newborn, Cancer research, lcsh:Q, Protein Kinases, 030217 neurology & neurosurgery
Abstract

MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, MlklD139V, that alters the two-helix ‘brace’ that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation of the salivary glands and mediastinum. The normal embryonic development of MlklD139V homozygotes until birth, and the absence of any overt phenotype in heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common human MLKL polymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, chronic recurrent multifocal osteomyelitis (CRMO)., Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region.

Published
2020

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