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The structure of iPLA2ß reveals dimeric active sites and suggests mechanisms of regulation and localization.
Malley, Konstantin R; Koroleva, Olga; Miller, Ian; Sanishvili, Ruslan; Jenkins, Christopher M; Gross, Richard W; Korolev, Sergey.
Afiliação
  • Malley KR; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.
  • Koroleva O; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.
  • Miller I; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.
  • Sanishvili R; GM/CA@APS, Advanced Photon Source, Argonne National Laboratory, Argonne, IL, 60439, USA.
  • Jenkins CM; Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8020, Saint Louis, MO, 63110, USA.
  • Gross RW; Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8020, Saint Louis, MO, 63110, USA.
  • Korolev S; Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
Nat Commun ; 9(1): 765, 2018 02 22.
Article em En | MEDLINE | ID: mdl-29472584
Calcium-independent phospholipase A2ß (iPLA2ß) 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 iPLA2ß-induced pathologic phenotypes remain poorly understood. Here, we present a crystal structure of iPLA2ß 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 iPLA2ß 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 iPLA2ß in the brain.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fosfolipases A2 do Grupo VI Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fosfolipases A2 do Grupo VI Idioma: En Ano de publicação: 2018 Tipo de documento: Article