| Structural highlights
Function
[VPS29_HUMAN] Essential component of the retromer complex, a complex required to retrieve lysosomal enzyme receptors (IGF2R and M6PR) from endosomes to the trans-Golgi network. Also required to regulate transcytosis of the polymeric immunoglobulin receptor (pIgR-pIgA). Has low protein phosphatase activity towards a serine-phosphorylated peptide derived from IGF2R (in vitro).[1] [TBCD5_HUMAN] May act as a GTPase-activating protein (GAP) for Rab family protein(s). May act as a GAP for RAB7A. Can displace RAB7A and retromer CSC subcomplex from the endosomal membrane to the cytosol; at least retromer displacement seems to require its catalytic activity (PubMed:19531583, PubMed:20923837). Required for retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN); the function seems to require its catalytic activity. Involved in regulation of autophagy (PubMed:22354992). May act as a molecular switch between endosomal and autophagosomal transport and is involved in reprogramming vesicle trafficking upon autophagy induction. Involved in the trafficking of ATG9A upon activation of autophagy. May regulate the recruitment of ATG9A-AP2-containing vesicles to autophagic membranes (PubMed:24603492).[2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Retromer is a membrane coat complex that is recruited to endosomes by the small GTPase Rab7 and sorting nexin 3. The timing of this interaction and consequent endosomal dynamics are thought to be regulated by the guanine nucleotide cycle of Rab7. Here we demonstrate that TBC1d5, a GTPase-activating protein (GAP) for Rab7, is a high-affinity ligand of the retromer cargo selective complex VPS26/VPS29/VPS35. The crystal structure of the TBC1d5 GAP domain bound to VPS29 and complementary biochemical and cellular data show that a loop from TBC1d5 binds to a conserved hydrophobic pocket on VPS29 opposite the VPS29-VPS35 interface. Additional data suggest that a distinct loop of the GAP domain may contact VPS35. Loss of TBC1d5 causes defective retromer-dependent trafficking of receptors. Our findings illustrate how retromer recruits a GAP, which is likely to be involved in the timing of Rab7 inactivation leading to membrane uncoating, with important consequences for receptor trafficking.
Structural and mechanistic insights into regulation of the retromer coat by TBC1d5.,Jia D, Zhang JS, Li F, Wang J, Deng Z, White MA, Osborne DG, Phillips-Krawczak C, Gomez TS, Li H, Singla A, Burstein E, Billadeau DD, Rosen MK Nat Commun. 2016 Nov 9;7:13305. doi: 10.1038/ncomms13305. PMID:27827364[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Verges M, Luton F, Gruber C, Tiemann F, Reinders LG, Huang L, Burlingame AL, Haft CR, Mostov KE. The mammalian retromer regulates transcytosis of the polymeric immunoglobulin receptor. Nat Cell Biol. 2004 Aug;6(8):763-9. Epub 2004 Jul 11. PMID:15247922 doi:10.1038/ncb1153
- ↑ Seaman MN, Harbour ME, Tattersall D, Read E, Bright N. Membrane recruitment of the cargo-selective retromer subcomplex is catalysed by the small GTPase Rab7 and inhibited by the Rab-GAP TBC1D5. J Cell Sci. 2009 Jul 15;122(Pt 14):2371-82. Epub 2009 Jun 16. PMID:19531583 doi:http://dx.doi.org/jcs.048686
- ↑ Harbour ME, Breusegem SY, Antrobus R, Freeman C, Reid E, Seaman MN. The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule dynamics. J Cell Sci. 2010 Nov 1;123(Pt 21):3703-17. doi: 10.1242/jcs.071472. Epub 2010 Oct, 5. PMID:20923837 doi:http://dx.doi.org/10.1242/jcs.071472
- ↑ Popovic D, Akutsu M, Novak I, Harper JW, Behrends C, Dikic I. Rab GTPase-activating proteins in autophagy: regulation of endocytic and autophagy pathways by direct binding to human ATG8 modifiers. Mol Cell Biol. 2012 May;32(9):1733-44. doi: 10.1128/MCB.06717-11. Epub 2012 Feb, 21. PMID:22354992 doi:http://dx.doi.org/10.1128/MCB.06717-11
- ↑ Popovic D, Dikic I. TBC1D5 and the AP2 complex regulate ATG9 trafficking and initiation of autophagy. EMBO Rep. 2014 Apr;15(4):392-401. doi: 10.1002/embr.201337995. Epub 2014 Mar 6. PMID:24603492 doi:http://dx.doi.org/10.1002/embr.201337995
- ↑ Seaman MN, Harbour ME, Tattersall D, Read E, Bright N. Membrane recruitment of the cargo-selective retromer subcomplex is catalysed by the small GTPase Rab7 and inhibited by the Rab-GAP TBC1D5. J Cell Sci. 2009 Jul 15;122(Pt 14):2371-82. Epub 2009 Jun 16. PMID:19531583 doi:http://dx.doi.org/jcs.048686
- ↑ Popovic D, Akutsu M, Novak I, Harper JW, Behrends C, Dikic I. Rab GTPase-activating proteins in autophagy: regulation of endocytic and autophagy pathways by direct binding to human ATG8 modifiers. Mol Cell Biol. 2012 May;32(9):1733-44. doi: 10.1128/MCB.06717-11. Epub 2012 Feb, 21. PMID:22354992 doi:http://dx.doi.org/10.1128/MCB.06717-11
- ↑ Popovic D, Dikic I. TBC1D5 and the AP2 complex regulate ATG9 trafficking and initiation of autophagy. EMBO Rep. 2014 Apr;15(4):392-401. doi: 10.1002/embr.201337995. Epub 2014 Mar 6. PMID:24603492 doi:http://dx.doi.org/10.1002/embr.201337995
- ↑ Jia D, Zhang JS, Li F, Wang J, Deng Z, White MA, Osborne DG, Phillips-Krawczak C, Gomez TS, Li H, Singla A, Burstein E, Billadeau DD, Rosen MK. Structural and mechanistic insights into regulation of the retromer coat by TBC1d5. Nat Commun. 2016 Nov 9;7:13305. doi: 10.1038/ncomms13305. PMID:27827364 doi:http://dx.doi.org/10.1038/ncomms13305
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