7xfr | pdb_00007xfr
Crystal structure of WIPI2b in complex with the second site of ATG16L1
Structural highlights
DiseaseWIPI2_HUMAN The disease is caused by variants affecting the gene represented in this entry. FunctionWIPI2_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:20505359, PubMed:28561066). Involved in an early step of the formation of preautophagosomal structures (PubMed:20505359, PubMed:28561066). Binds and is activated by phosphatidylinositol 3-phosphate (PtdIns3P) forming on membranes of the endoplasmic reticulum upon activation of the upstream ULK1 and PI3 kinases (PubMed:28561066). Mediates ER-isolation membranes contacts by interacting with the ULK1:RB1CC1 complex and PtdIns3P (PubMed:28890335). Once activated, WIPI2 recruits at phagophore assembly sites the ATG12-ATG5-ATG16L1 complex that directly controls the elongation of the nascent autophagosomal membrane (PubMed:20505359, PubMed:28561066).[1] [2] [3] [4] Recruits the ATG12-ATG5-ATG16L1 complex to omegasomes and preautophagosomal structures, resulting in ATG8 family proteins lipidation and starvation-induced autophagy. Isoform 4 is also required for autophagic clearance of pathogenic bacteria. Isoform 4 binds the membrane surrounding Salmonella and recruits the ATG12-5-16L1 complex, initiating LC3 conjugation, autophagosomal membrane formation, and engulfment of Salmonella.[5] Publication Abstract from PubMedMacroautophagy plays crucial roles in the regulation of cellular physiology and requires de novo synthesis of double-membrane autophagosomes, which relies on a specific interaction between autophagy-related 16L1 (ATG16L1) and WD repeat domain phosphoinositide-interacting protein 2b (WIPI2b). However, the molecular mechanism governing the interaction of ATG16L1 with WIPI2b remains elusive. Here, we find that ATG16L1 has two distinct binding sites for interacting with WIPI2b, the previously reported WIPI2b-binding site (WBS1) and the previously unidentified site (WBS2). We determine the crystal structures of WIPI2b with ATG16L1 WBS1 and WBS2, respectively, and elucidate the molecular mechanism underpinning the recruitment of ATG16L1 by WIPI2b. Moreover, we uncover that ATG16L1 WBS2 and its binding mode with WIPI2b is well conserved from yeast to mammals, unlike ATG16L1 WBS1. Last, our cell-based functional assays demonstrate that both ATG16L1 WBS1 and WBS2 are required for the effective autophagic flux. In conclusion, our findings provide mechanistic insights into the key ATG16L1/WIPI2b interaction in autophagy. ATG16L1 adopts a dual-binding site mode to interact with WIPI2b in autophagy.,Gong X, Wang Y, Tang Y, Wang Y, Zhang M, Li M, Zhang Y, Pan L Sci Adv. 2023 Mar;9(9):eadf0824. doi: 10.1126/sciadv.adf0824. Epub 2023 Mar 1. PMID:36857448[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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