8VYB
Cryo-EM structure of human core Rab3GAP1/2 complex
Summary for 8VYB
| Entry DOI | 10.2210/pdb8vyb/pdb |
| EMDB information | 43655 |
| Descriptor | Isoform 2 of Rab3 GTPase-activating protein catalytic subunit, Rab3 GTPase-activating protein non-catalytic subunit (2 entities in total) |
| Functional Keywords | complex, gap, gef, rab3gap, lipid droplet, er, rab regulator, membrane trafficking, cytosolic protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 181868.61 |
| Authors | |
| Primary citation | Fairlie, G.M.J.,Nguyen, K.M.,Nam, S.E.,Shaw, A.L.,Parson, M.A.H.,Shariati, H.R.,Wang, X.,Jenkins, M.L.,Gong, M.,Burke, J.E.,Yip, C.K. Biochemical and structural characterization of Rab3GAP reveals insights into Rab18 nucleotide exchange activity. Nat Commun, 16:479-479, 2025 Cited by PubMed Abstract: The heterodimeric Rab3GAP complex is a guanine nucleotide exchange factor (GEF) for the Rab18 GTPase that regulates lipid droplet metabolism, ER-to-Golgi trafficking, secretion, and autophagy. Why both subunits of Rab3GAP are required for Rab18 GEF activity and the molecular basis of how Rab3GAP engages and activates its cognate substrate are unknown. Here we show that human Rab3GAP is conformationally flexible and potentially autoinhibited by the C-terminal domain of its Rab3GAP2 subunit. Our high-resolution structure of the catalytic core of Rab3GAP, determined by cryo-EM, shows that the Rab3GAP2 N-terminal domain binds Rab3GAP1 via an extensive interface. AlphaFold3 modelling analysis together with targeted mutagenesis and in vitro activity assay reveal that Rab3GAP likely engages its substrate Rab18 through an interface away from the switch and interswitch regions. Lastly, we find that three Warburg Micro Syndrome-associated missense mutations do not affect the overall architecture of Rab3GAP but instead likely interfere with substrate binding. PubMed: 39779760DOI: 10.1038/s41467-025-55828-8 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.37 Å) |
Structure validation
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