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Structure paper

TitleA novel RAB5 binding site in human VPS34-CII that is likely the primordial site in eukaryotic evolution.
Journal, issue, pagesElife, Vol. 15, Year 2026
Publish dateMay 28, 2026
AuthorsSaule Spokaite / Yohei Ohashi / Maxime Bourguet / Antoine Nicolas Dessus / Roger L Williams /
PubMed AbstractRAB5-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 ...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.
External linksElife / PubMed:42207670 / PubMed Central
MethodsEM (single particle)
Resolution3.15 - 4.09 Å
Structure data

EMDB-54312: VPS34-CII (VPS34 199-REIE-202 to 199-AAAA-202 mutant) bound to RAB5A (Q79L, focused refinement on the adaptor arm)
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-54313: VPS34-CII (VPS34 199-REIE-202 to 199-AAAA-202 mutant) bound to RAB5A (Q79L, focused refinement on the kinase arm)
Method: EM (single particle) / Resolution: 3.15 Å

EMDB-54314: VPS34-CII (VPS34 199-REIE-202 to 199-AAAA-202 mutant) bound to RAB5A (Q79L), focused refinement on the base of the complex
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-54315: VPS34-CII (VPS34 199-REIE-202 to 199-AAAA-202 mutant) bound to RAB5A (Q79L, focused refinement on the interface between RAB5A and VPS34)
Method: EM (single particle) / Resolution: 3.25 Å

EMDB-54316: VPS34-CII (VPS34 199-REIE-202 > 199-AAAA-202 mutant) bound to RAB5A-GTP (Q79L), consensus refinement
Method: EM (single particle) / Resolution: 3.43 Å

EMDB-54317: VPS34-CII (VPS34 199-REIE-202 > 199-AAAA-202 mutant) bound to RAB5A-GTP (Q79L); unsharpened composite map
Method: EM (single particle) / Resolution: 3.15 Å

EMDB-54318: VPS34-CII (VPS34 199-REIE-202 to 199-ERIR-202 mutant) bound to RAB5A (Q79L) on the VPS15 subunit, focused refinement on the kinase arm
Method: EM (single particle) / Resolution: 3.55 Å

EMDB-54319: VPS34-CII (VPS34 199-REIE-202 to 199-ERIR-202 mutant) bound to RAB5A (Q79L) on the VPS15 subunit, focused refinement on the adaptor arm
Method: EM (single particle) / Resolution: 4.09 Å

EMDB-54320: VPS34-CII (VPS34 199-REIE-202 to 199-ERIR-202 mutant) bound to RAB5A (Q79L) on the VPS15 subunit, focused refinement of the RAB5A interface with VPS15
Method: EM (single particle) / Resolution: 3.52 Å

EMDB-54321: VPS34-CII (VPS34 199-REIE-202 to 199-ERIR-202 mutant) bound to RAB5A (Q79L) on the VPS15 subunit, consensus refinement
Method: EM (single particle) / Resolution: 3.68 Å

EMDB-54322: VPS34-CII (VPS34 199-REIE-202 to 199-ERIR-202 mutant) bound to RAB5A (Q79L) on the VPS15 subunit; unsharpened composite map
Method: EM (single particle) / Resolution: 3.52 Å

54358

9rx5

EMDB-54358: VPS34-CII (VPS34 199-REIE-202 to 199-AAAA-202 mutant) bound to RAB5A (Q79L), primary composite map processed with CryoTEN
PDB-9rx5: VPS34-CII (VPS34 199-REIE-202 to 199-AAAA-202 mutant) bound to RAB5A (Q79L)
Method: EM (single particle) / Resolution: 3.15 Å

54359

9rx6

EMDB-54359: VPS34-CII (VPS34 199-REIE-202 to 199-ERIR-202 mutant) bound to RAB5A (Q79L) on the VPS15 subunit, composite map processed with CryoTEN.
PDB-9rx6: VPS34-CII (VPS34 199-REIE-202 to 199-ERIR-202 mutant) bound to RAB5A (Q79L) on the VPS15 subunit
Method: EM (single particle) / Resolution: 3.52 Å

54361

9rx8

EMDB-54361: Apo VPS34-CII (VPS34/VPS15/BECLIN1/UVRAG), consensus refinement map processed with CryoTEN
PDB-9rx8: Apo VPS34-CII (VPS34/VPS15/BECLIN1/UVRAG)
Method: EM (single particle) / Resolution: 3.87 Å

54362

9rx9

EMDB-54362: VPS34-CII bound to RAB5A-GTP 1-212 (C19S, C63S, Q79L) on the VPS34 subunit, primary map processed with CryoTEN
PDB-9rx9: VPS34-CII bound to RAB5A-GTP 1-212 (C19S, C63S, Q79L) on the VPS34 subunit
Method: EM (single particle) / Resolution: 3.99 Å

54363

9rxa

EMDB-54363: VPS34-CII bound to RAB5A-GTP 1-212 (C19S, C63S, Q79L) on the VPS15 subunit, primary map processed with CryoTEN
PDB-9rxa: VPS34-CII bound to RAB5A-GTP 1-212 (C19S, C63S, Q79L) on the VPS15 subunit
Method: EM (single particle) / Resolution: 4.0 Å

54364

9rxb

EMDB-54364: VPS34-CII (VPS34/VPS15/BECLIN1/UVRAG) bound to RAB5A (Q79L) on the VPS34 and VPS15 subunits, primary map processed with CryoTEN
PDB-9rxb: VPS34-CII (VPS34/VPS15/BECLIN1/UVRAG) bound to RAB5A (Q79L) on the VPS34 and VPS15 subunits
Method: EM (single particle) / Resolution: 4.03 Å

Chemicals

ChemComp-MYR:
MYRISTIC ACID

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM

Source
  • homo sapiens (human)
KeywordsENDOCYTOSIS / Lipid kinase / GTPase / kinase / autophagy / endocytic trafficking / SIGNALING PROTEIN / endocytic sorting / endosome maturation

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