9RX9
VPS34-CII bound to RAB5A-GTP 1-212 (C19S, C63S, Q79L) on the VPS34 subunit
Summary for 9RX9
| Entry DOI | 10.2210/pdb9rx9/pdb |
| EMDB information | 54362 |
| Descriptor | Phosphatidylinositol 3-kinase catalytic subunit type 3, GUANOSINE-5'-TRIPHOSPHATE, Phosphoinositide 3-kinase regulatory subunit 4, ... (10 entities in total) |
| Functional Keywords | lipid kinase, gtpase, kinase, endocytic trafficking, endosome maturation, signaling protein, endocytosis |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 411224.47 |
| Authors | Spokaite, S.,Ohashi, Y.,Dessus, A.N.,Bourguet, M.,Williams, R.L. (deposition date: 2025-07-10, release date: 2026-06-03, Last modification date: 2026-06-10) |
| Primary citation | Spokaite, S.,Ohashi, Y.,Bourguet, M.,Dessus, A.N.,Williams, R.L. A novel RAB5 binding site in human VPS34-CII that is likely the primordial site in eukaryotic evolution. Elife, 15:-, 2026 Cited by PubMed Abstract: RAB5-GTP activation of the multiprotein VPS34 complex II (VPS34-CII) is critical for endosomal sorting and maturation, phagocytosis, and receptor downregulation. RAB5-GTP activates VPS34-CII by binding to a helical insertion in the C2 domain of VPS34 on the BECLIN1/UVRAG-containing adaptor arm of the complex. The autophagy complex, VPS34 complex I (VPS34-CI), features a unique ATG14L subunit in place of the VPS34-CII UVRAG subunit, and we found that this distorts the adaptor arm to alter the VPS34 RAB-GTPase binding pocket so that it preferentially binds RAB1-GTP. Surprisingly, our higher-resolution single-particle cryo-EM structure of VPS34-CII showed a second RAB5-GTP binding site on the VPS15 solenoid region. This site (VPS15-RAB5-site) appears to be the primordial RAB5-binding region. A mutant in the helical insertion of the C2 domain of human VPS34 that mimics the sequence abolishes RAB5 binding to VPS34. Mutation of the VPS15-RAB5-site ortholog in VPS15 resulted in defective CPY sorting, loss of colocalisation with the RAB5 ortholog Vps21, and loss of binding to Vps21 in vitro. Evolutionary expansion from one to two RAB5-orthologue binding sites may have increased membrane binding and VPS34-CII activity to adapt to more complex endocytic systems. PubMed: 42207670DOI: 10.7554/eLife.110040 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.99 Å) |
Structure validation
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