8vyb

From Proteopedia

(Difference between revisions)

Current revision

Cryo-EM structure of human core Rab3GAP1/2 complex

Structural highlights

8vyb is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.37Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

RB3GP_HUMAN Cataract-intellectual disability-hypogonadism syndrome;Micro syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.

Function

RB3GP_HUMAN Catalytic subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which has GTPase-activating protein (GAP) activity towards various Rab3 subfamily members (RAB3A, RAB3B, RAB3C and RAB3D), RAB5A and RAB43, and guanine nucleotide exchange factor (GEF) activity towards RAB18 (PubMed:10859313, PubMed:24891604, PubMed:9030515). As part of the Rab3GAP complex, acts as a GAP for Rab3 proteins by converting active RAB3-GTP to the inactive form RAB3-GDP (PubMed:10859313). Rab3 proteins are involved in regulated exocytosis of neurotransmitters and hormones (PubMed:15696165). The Rab3GAP complex, acts as a GEF for RAB18 by promoting the conversion of inactive RAB18-GDP to the active form RAB18-GTP (PubMed:24891604). Required for recruiting and activating RAB18 at the endoplasmic reticulum (ER) membrane where it maintains proper ER structure (PubMed:24891604). Required for normal eye and brain development (PubMed:15696165, PubMed:23420520). May participate in neurodevelopmental processes such as proliferation, migration and differentiation before synapse formation, and non-synaptic vesicular release of neurotransmitters (PubMed:9030515, PubMed:9852129).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

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.

Biochemical and structural characterization of Rab3GAP reveals insights into Rab18 nucleotide exchange activity.,Fairlie GMJ, Nguyen KM, Nam SE, Shaw AL, Parson MAH, Shariati HR, Wang X, Jenkins ML, Gong M, Burke JE, Yip CK Nat Commun. 2025 Jan 8;16(1):479. doi: 10.1038/s41467-025-55828-8. PMID:39779760^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Clabecq A, Henry JP, Darchen F. Biochemical characterization of Rab3-GTPase-activating protein reveals a mechanism similar to that of Ras-GAP. J Biol Chem. 2000 Oct 13;275(41):31786-91. PMID:10859313 doi:10.1074/jbc.M003705200
↑ Aligianis IA, Johnson CA, Gissen P, Chen D, Hampshire D, Hoffmann K, Maina EN, Morgan NV, Tee L, Morton J, Ainsworth JR, Horn D, Rosser E, Cole TR, Stolte-Dijkstra I, Fieggen K, Clayton-Smith J, Mégarbané A, Shield JP, Newbury-Ecob R, Dobyns WB, Graham JM Jr, Kjaer KW, Warburg M, Bond J, Trembath RC, Harris LW, Takai Y, Mundlos S, Tannahill D, Woods CG, Maher ER. Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome. Nat Genet. 2005 Mar;37(3):221-3. PMID:15696165 doi:10.1038/ng1517
↑ Handley MT, Morris-Rosendahl DJ, Brown S, Macdonald F, Hardy C, Bem D, Carpanini SM, Borck G, Martorell L, Izzi C, Faravelli F, Accorsi P, Pinelli L, Basel-Vanagaite L, Peretz G, Abdel-Salam GM, Zaki MS, Jansen A, Mowat D, Glass I, Stewart H, Mancini G, Lederer D, Roscioli T, Giuliano F, Plomp AS, Rolfs A, Graham JM, Seemanova E, Poo P, García-Cazorla A, Edery P, Jackson IJ, Maher ER, Aligianis IA. Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in warburg micro syndrome and Martsolf syndrome. Hum Mutat. 2013 May;34(5):686-96. PMID:23420520 doi:10.1002/humu.22296
↑ Gerondopoulos A, Bastos RN, Yoshimura S, Anderson R, Carpanini S, Aligianis I, Handley MT, Barr FA. Rab18 and a Rab18 GEF complex are required for normal ER structure. J Cell Biol. 2014 Jun 9;205(5):707-20. PMID:24891604 doi:10.1083/jcb.201403026
↑ Fukui K, Sasaki T, Imazumi K, Matsuura Y, Nakanishi H, Takai Y. Isolation and characterization of a GTPase activating protein specific for the Rab3 subfamily of small G proteins. J Biol Chem. 1997 Feb 21;272(8):4655-8. PMID:9030515 doi:10.1074/jbc.272.8.4655
↑ Oishi H, Sasaki T, Nagano F, Ikeda W, Ohya T, Wada M, Ide N, Nakanishi H, Takai Y. Localization of the Rab3 small G protein regulators in nerve terminals and their involvement in Ca2+-dependent exocytosis. J Biol Chem. 1998 Dec 18;273(51):34580-5. PMID:9852129 doi:10.1074/jbc.273.51.34580
↑ Fairlie GMJ, Nguyen KM, Nam SE, Shaw AL, Parson MAH, Shariati HR, Wang X, Jenkins ML, Gong M, Burke JE, Yip CK. Biochemical and structural characterization of Rab3GAP reveals insights into Rab18 nucleotide exchange activity. Nat Commun. 2025 Jan 8;16(1):479. PMID:39779760 doi:10.1038/s41467-025-55828-8

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8vyb"

Categories: Homo sapiens | Large Structures | Nguyen KM | Yip CK

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8vyb is ON HOLD
+==Cryo-EM structure of human core Rab3GAP1/2 complex==
+<StructureSection load='8vyb' size='340' side='right'caption='[[8vyb]], [[Resolution|resolution]] 3.37&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8vyb]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8VYB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8VYB FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.37&#8491;</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8vyb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8vyb OCA], [https://pdbe.org/8vyb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8vyb RCSB], [https://www.ebi.ac.uk/pdbsum/8vyb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8vyb ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/RB3GP_HUMAN RB3GP_HUMAN] Cataract-intellectual disability-hypogonadism syndrome;Micro syndrome. The disease is caused by variants affecting the gene represented in this entry.  The disease is caused by variants affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/RB3GP_HUMAN RB3GP_HUMAN] Catalytic subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which has GTPase-activating protein (GAP) activity towards various Rab3 subfamily members (RAB3A, RAB3B, RAB3C and RAB3D), RAB5A and RAB43, and guanine nucleotide exchange factor (GEF) activity towards RAB18 (PubMed:10859313, PubMed:24891604, PubMed:9030515). As part of the Rab3GAP complex, acts as a GAP for Rab3 proteins by converting active RAB3-GTP to the inactive form RAB3-GDP (PubMed:10859313). Rab3 proteins are involved in regulated exocytosis of neurotransmitters and hormones (PubMed:15696165). The Rab3GAP complex, acts as a GEF for RAB18 by promoting the conversion of inactive RAB18-GDP to the active form RAB18-GTP (PubMed:24891604). Required for recruiting and activating RAB18 at the endoplasmic reticulum (ER) membrane where it maintains proper ER structure (PubMed:24891604). Required for normal eye and brain development (PubMed:15696165, PubMed:23420520). May participate in neurodevelopmental processes such as proliferation, migration and differentiation before synapse formation, and non-synaptic vesicular release of neurotransmitters (PubMed:9030515, PubMed:9852129).<ref>PMID:10859313</ref> <ref>PMID:15696165</ref> <ref>PMID:23420520</ref> <ref>PMID:24891604</ref> <ref>PMID:9030515</ref> <ref>PMID:9852129</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+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.
-Authors:
+Biochemical and structural characterization of Rab3GAP reveals insights into Rab18 nucleotide exchange activity.,Fairlie GMJ, Nguyen KM, Nam SE, Shaw AL, Parson MAH, Shariati HR, Wang X, Jenkins ML, Gong M, Burke JE, Yip CK Nat Commun. 2025 Jan 8;16(1):479. doi: 10.1038/s41467-025-55828-8. PMID:39779760<ref>PMID:39779760</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 8vyb" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Nguyen KM]]
+[[Category: Yip CK]]

8vyb

From Proteopedia

Current revision

Cryo-EM structure of human core Rab3GAP1/2 complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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