TY  - JOUR
A1  - Lo, Wen-Ting
A1  - Zhang, Yingyi
A1  - Vadas, Oscar
A1  - Roske, Yvette
A1  - Gulluni, Federico
A1  - De Santis, Maria Chiara
A1  - Vujicic Zagar, Andreja
A1  - Stephanowitz, Heike
A1  - Hirsch, Emilio
A1  - Liu, Fan
A1  - Daumke, Oliver
A1  - Kudryashev, Mikhail
A1  - Haucke, Volker
T1  - Structural basis of phosphatidylinositol 3-kinase C2α function
T2  - Nature structural & molecular biology
N2  - Phosphatidylinositol 3-kinase type 2α (PI3KC2α) is an essential member of the structurally unresolved class II PI3K family with crucial functions in lipid signaling, endocytosis, angiogenesis, viral replication, platelet formation and a role in mitosis. The molecular basis of these activities of PI3KC2α is poorly understood. Here, we report high-resolution crystal structures as well as a 4.4-Å cryogenic-electron microscopic (cryo-EM) structure of PI3KC2α in active and inactive conformations. We unravel a coincident mechanism of lipid-induced activation of PI3KC2α at membranes that involves large-scale repositioning of its Ras-binding and lipid-binding distal Phox-homology and C-C2 domains, and can serve as a model for the entire class II PI3K family. Moreover, we describe a PI3KC2α-specific helical bundle domain that underlies its scaffolding function at the mitotic spindle. Our results advance our understanding of PI3K biology and pave the way for the development of specific inhibitors of class II PI3K function with wide applications in biomedicine.
KW  - Cryoelectron microscopy
KW  - Endosomes
KW  - Membrane lipids
KW  - Phospholipids
KW  - X-ray crystallography
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63278
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-632782
SN  - 1545-9985
N1  - Open access funding provided by Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
N1  - Funding: FMP
VL  - 29
IS  - 3
SP  - 218
EP  - 228
PB  - Nature Publishing Group
CY  - London [u.a.]
ER  -