6klr
Crystal structure of human WIPI3 in complex with the WIR-peptide from ATG2A
Structural highlights
DiseaseWIPI3_HUMAN The disease may be caused by mutations affecting the gene represented in this entry. FunctionATG2A_HUMAN Involved in autophagosome assembly, regulating the size of nascent autophagosomes (PubMed:28561066). Also regulates lipid droplets morphology and distribution within the cell (PubMed:22219374, PubMed:28561066).[1] [2] WIPI3_HUMAN Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation (PubMed:28561066). Binds phosphatidylinositol 3-phosphate (PtdIns3P) forming on membranes of the endoplasmic reticulum upon activation of the upstream ULK1 and PI3 kinases and is recruited at phagophore assembly sites where it regulates the elongation of nascent phagophores downstream of WIPI2 (PubMed:28561066). In the cellular response to starvation, may also function together with the TSC1-TSC2 complex and RB1CC1 in the inhibition of the mTORC1 signaling pathway (PubMed:28503735).[3] [4] Publication Abstract from PubMedWIPI proteins (WIPI1-4) are mammalian PROPPIN family phosphoinositide effectors essential for autophagosome biogenesis. In addition to phosphoinositides, WIPI proteins can recognize a linear WIPI-interacting-region (WIR)-motif, but the underlying mechanism is poorly understood. Here, we determine the structure of WIPI3 in complex with the WIR-peptide from ATG2A. Unexpectedly, the WIR-peptide entwines around the WIPI3 seven-bladed beta-propeller and binds to three sites in blades 1-3. The N-terminal part of the WIR-peptide forms a short strand that augments the periphery of blade 2, the middle segment anchors into an inter-blade hydrophobic pocket between blades 2-3, and the C-terminal aromatic tail wedges into another tailored pocket between blades 1-2. Mutations in three peptide-binding sites disrupt the interactions between WIPI3/4 and ATG2A and impair the ATG2A-mediated autophagic process. Thus, WIPI proteins recognize the WIR-motif by multi-sites in multi-blades and this multi-site-mediated peptide-recognition mechanism could be applicable to other PROPPIN proteins. Multi-site-mediated entwining of the linear WIR-motif around WIPI beta-propellers for autophagy.,Ren J, Liang R, Wang W, Zhang D, Yu L, Feng W Nat Commun. 2020 Jun 1;11(1):2702. doi: 10.1038/s41467-020-16523-y. PMID:32483132[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
