The structure of iPLA2β reveals dimeric active sites and suggests mechanisms of regulation and localization
| Autor: | Richard W. Gross, Konstantin R. Malley, Ian J. Miller, Sergey Korolev, Ruslan Sanishvili, Christopher M. Jenkins, Olga Koroleva |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Regulation of gene expression Multidisciplinary Calmodulin biology Chemistry Science General Physics and Astronomy General Chemistry Plasma protein binding General Biochemistry Genetics and Molecular Biology 3. Good health Transport protein Cell biology 03 medical and health sciences 030104 developmental biology Transacylation Membrane protein biology.protein Ankyrin repeat lcsh:Q lcsh:Science Cellular localization |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-11 (2018) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-018-03193-0 |
| Popis: | Calcium-independent phospholipase A2β (iPLA2β) regulates important physiological processes including inflammation, calcium homeostasis and apoptosis. It is genetically linked to neurodegenerative disorders including Parkinson’s disease. Despite its known enzymatic activity, the mechanisms underlying iPLA2β-induced pathologic phenotypes remain poorly understood. Here, we present a crystal structure of iPLA2β that significantly revises existing mechanistic models. The catalytic domains form a tight dimer. They are surrounded by ankyrin repeat domains that adopt an outwardly flared orientation, poised to interact with membrane proteins. The closely integrated active sites are positioned for cooperative activation and internal transacylation. The structure and additional solution studies suggest that both catalytic domains can be bound and allosterically inhibited by a single calmodulin. These features suggest mechanisms of iPLA2β cellular localization and activity regulation, providing a basis for inhibitor development. Furthermore, the structure provides a framework to investigate the role of neurodegenerative mutations and the function of iPLA2β in the brain. |
| Databáze: | OpenAIRE |
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