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==Structure of human Rubicon RH domain in complex with GTP-bound Rab7==
<StructureSection load='6wcw' size='340' side='right'caption='[[6wcw]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6wcw]] 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=6WCW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6WCW FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=6wcw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wcw OCA], [https://pdbe.org/6wcw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6wcw RCSB], [https://www.ebi.ac.uk/pdbsum/6wcw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6wcw ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/RAB7A_HUMAN RAB7A_HUMAN] Defects in RAB7A are the cause of Charcot-Marie-Tooth disease type 2B (CMT2B) [MIM:[https://omim.org/entry/600882 600882]; also known as hereditary motor and sensory neuropathy II (HMSN2). CMT2B is a form of Charcot-Marie-Tooth disease, the most common inherited disorder of the peripheral nervous system. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathy or CMT1, and primary peripheral axonal neuropathy or CMT2. Neuropathies of the CMT2 group are characterized by signs of axonal regeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2B is clinically characterized by marked distal muscle weakness and a high frequency of foot ulcers, infections and amputations of the toes. CMT2B inheritance is autosomal dominant.<ref>PMID:12545426</ref> <ref>PMID:15455439</ref> <ref>PMID:17060578</ref> <ref>PMID:21151572</ref> 
== Function ==
[https://www.uniprot.org/uniprot/RAB7A_HUMAN RAB7A_HUMAN] Key regulator in endo-lysosomal trafficking. Governs early-to-late endosomal maturation, microtubule minus-end as well as plus-end directed endosomal migration and positioning, and endosome-lysosome transport through different protein-protein interaction cascades. Plays a central role, not only in endosomal traffic, but also in many other cellular and physiological events, such as growth-factor-mediated cell signaling, nutrient-transportor mediated nutrient uptake, neurotrophin transport in the axons of neurons and lipid metabolism. Also involved in regulation of some specialized endosomal membrane trafficking, such as maturation of melanosomes, pathogen-induced phagosomes (or vacuoles) and autophagosomes. Plays a role in the maturation and acidification of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis. Plays a role in the fusion of phagosomes with lysosomes. Plays important roles in microbial pathogen infection and survival, as well as in participating in the life cycle of viruses. Microbial pathogens possess survival strategies governed by RAB7A, sometimes by employing RAB7A function (e.g. Salmonella) and sometimes by excluding RAB7A function (e.g. Mycobacterium). In concert with RAC1, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts. Controls the endosomal trafficking and neurite outgrowth signaling of NTRK1/TRKA. Regulates the endocytic trafficking of the EGF-EGFR complex by regulating its lysosomal degradation.<ref>PMID:11179213</ref> <ref>PMID:12944476</ref> <ref>PMID:14617358</ref> <ref>PMID:21255211</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Rubicon is a potent negative regulator of autophagy and a potential target for autophagy-inducing therapeutics. Rubicon-mediated inhibition of autophagy requires the interaction of the C-terminal Rubicon homology (RH) domain of Rubicon with Rab7-GTP. Here we report the 2.8-A crystal structure of the Rubicon RH domain in complex with Rab7-GTP. Our structure reveals a fold for the RH domain built around four zinc clusters. The switch regions of Rab7 insert into pockets on the surface of the RH domain in a mode that is distinct from those of other Rab-effector complexes. Rubicon residues at the dimer interface are required for Rubicon and Rab7 to colocalize in living cells. Mutation of Rubicon RH residues in the Rab7-binding site restores efficient autophagic flux in the presence of overexpressed Rubicon, validating the Rubicon RH domain as a promising therapeutic target.

Structural basis for autophagy inhibition by the human Rubicon-Rab7 complex.,Bhargava HK, Tabata K, Byck JM, Hamasaki M, Farrell DP, Anishchenko I, DiMaio F, Im YJ, Yoshimori T, Hurley JH Proc Natl Acad Sci U S A. 2020 Jul 6. pii: 2008030117. doi:, 10.1073/pnas.2008030117. PMID:32632011<ref>PMID:32632011</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6wcw" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ras-related protein Rab 3D structures|Ras-related protein Rab 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Anishchenko I]]
[[Category: Bhargava HK]]
[[Category: Byck JM]]
[[Category: DiMaio F]]
[[Category: Farrell DP]]
[[Category: Hurley JH]]
[[Category: Im YJ]]