期刊
AUTOPHAGY
卷 12, 期 11, 页码 2129-2144出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2016.1226736
关键词
Atg14; Atg38; Beclin 1; complex I; crystal structure; EM structure; NRBF2; Vps15; Vps30; Vps34
类别
资金
- MRC
- Cambridge Overseas trust
- EMBL Interdisciplinary Postdoc (EIPOD) fellowships under Marie Curie Actions [PCOFUND-GA-2008-229597]
- Marie-Sklodowska-Curie Intra-European fellowship [PIEF-GA-2012-331285]
- British Heart Foundation [PG11/109/29247]
- BBSRC [BB/K019155/1]
- Medical Research Council [MC_U105184308]
- BBSRC [BBS/E/B/000C0413] Funding Source: UKRI
- MRC [MC_U105184308] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/K019155/1, BBS/E/B/000C0413] Funding Source: researchfish
- Medical Research Council [1358691, 1274329] Funding Source: researchfish
The phosphatidylinositol 3-kinase Vps34 is part of several protein complexes. The structural organization of heterotetrameric complexes is starting to emerge, but little is known about organization of additional accessory subunits that interact with these assemblies. Combining hydrogen-deuterium exchange mass spectrometry (HDX-MS), X-ray crystallography and electron microscopy (EM), we have characterized Atg38 and its human ortholog NRBF2, accessory components of complex I consisting of Vps15-Vps34-Vps30/Atg6-Atg14 (yeast) and PIK3R4/VPS15-PIK3C3/VPS34-BECN1/Beclin 1-ATG14 (human). HDX-MS shows that Atg38 binds the Vps30-Atg14 subcomplex of complex I, using mainly its N-terminal MIT domain and bridges the coiled-coil I regions of Atg14 and Vps30 in the base of complex I. The Atg38 C-terminal domain is important for localization to the phagophore assembly site (PAS) and homodimerization. Our 2.2 angstrom resolution crystal structure of the Atg38 C-terminal homodimerization domain shows 2 segments of -helices assembling into a mushroom-like asymmetric homodimer with a 4-helix cap and a parallel coiled-coil stalk. One Atg38 homodimer engages a single complex I. This is in sharp contrast to human NRBF2, which also forms a homodimer, but this homodimer can bridge 2 complex I assemblies.
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