| Structural highlights
Disease
[TBC23_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.
Function
[TBC23_HUMAN] Putative Rab GTPase-activating protein which plays a role in vesicular trafficking (PubMed:28823707). Involved in endosome-to-Golgi trafficking. Acts as a bridging protein by binding simultaneously to golgins, including GOLGA1 and GOLGA4, located at the trans-Golgi, and to the WASH complex, located on endosome-derived vesicles (PubMed:29084197, PubMed:29426865). Together with WDR11 complex facilitates the golgin-mediated capture of vesicles generated using AP-1 (PubMed:29426865). Plays a role in brain development, including in cortical neuron positioning (By similarity). May also be important for neurite outgrowth, possibly through its involvement in membrane trafficking and cargo delivery, 2 processes that are essential for axonal and dendritic growth (By similarity). May act as a general inhibitor of innate immunity signaling, strongly inhibiting multiple TLR and dectin/CLEC7A-signaling pathways. Does not alter initial activation events, but instead affects maintenance of inflammatory gene expression several hours after bacterial lipopolysaccharide (LPS) challenge (By similarity).[UniProtKB:Q8K0F1][1] [2] [3]
Publication Abstract from PubMed
Pontocerebellar hypoplasia (PCH) is a group of neurological disorders that affect the development of the brain, in particular, the pons and cerebellum. Homozygous mutations of TBC1D23 have been found recently to lead to PCH; however, the underlying molecular mechanisms remain unclear. Here, we show that the crystal structure of the TBC1D23 C-terminal domain adopts a Pleckstrin homology domain fold and selectively binds to phosphoinositides, in particular, PtdIns(4)P, through one surface while binding FAM21 via the opposite surface. Mutation of key residues of TBC1D23 or FAM21 selectively disrupts the endosomal vesicular trafficking toward the Trans-Golgi Network. Finally, using the zebrafish model, we show that PCH patient-derived mutants, impacting either phosphoinositide binding or FAM21 binding, lead to abnormal neuronal growth and brain development. Taken together, our data provide a molecular basis for the interaction between TBC1D23 and FAM21, and suggest a plausible role for PtdIns(4)P in the TBC1D23-mediating endosome-to-TGN trafficking pathway. Defects in this trafficking pathway are, at least partially, responsible for the pathogenesis of certain types of PCH.
Structural and functional studies of TBC1D23 C-terminal domain provide a link between endosomal trafficking and PCH.,Huang W, Liu Z, Yang F, Zhou H, Yong X, Yang X, Zhou Y, Xue L, Zhang Y, Liu D, Meng W, Zhang W, Zhang X, Shen X, Sun Q, Li L, Ma C, Wei Y, Billadeau DD, Mo X, Jia D Proc Natl Acad Sci U S A. 2019 Oct 17. pii: 1909316116. doi:, 10.1073/pnas.1909316116. PMID:31624125[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ivanova EL, Mau-Them FT, Riazuddin S, Kahrizi K, Laugel V, Schaefer E, de Saint Martin A, Runge K, Iqbal Z, Spitz MA, Laura M, Drouot N, Gerard B, Deleuze JF, de Brouwer APM, Razzaq A, Dollfus H, Assir MZ, Nitchke P, Hinckelmann MV, Ropers H, Riazuddin S, Najmabadi H, van Bokhoven H, Chelly J. Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development. Am J Hum Genet. 2017 Sep 7;101(3):428-440. doi: 10.1016/j.ajhg.2017.07.010. Epub , 2017 Aug 17. PMID:28823707 doi:http://dx.doi.org/10.1016/j.ajhg.2017.07.010
- ↑ Shin JJH, Gillingham AK, Begum F, Chadwick J, Munro S. TBC1D23 is a bridging factor for endosomal vesicle capture by golgins at the trans-Golgi. Nat Cell Biol. 2017 Dec;19(12):1424-1432. doi: 10.1038/ncb3627. Epub 2017 Oct 30. PMID:29084197 doi:http://dx.doi.org/10.1038/ncb3627
- ↑ Navarro Negredo P, Edgar JR, Manna PT, Antrobus R, Robinson MS. The WDR11 complex facilitates the tethering of AP-1-derived vesicles. Nat Commun. 2018 Feb 9;9(1):596. doi: 10.1038/s41467-018-02919-4. PMID:29426865 doi:http://dx.doi.org/10.1038/s41467-018-02919-4
- ↑ Huang W, Liu Z, Yang F, Zhou H, Yong X, Yang X, Zhou Y, Xue L, Zhang Y, Liu D, Meng W, Zhang W, Zhang X, Shen X, Sun Q, Li L, Ma C, Wei Y, Billadeau DD, Mo X, Jia D. Structural and functional studies of TBC1D23 C-terminal domain provide a link between endosomal trafficking and PCH. Proc Natl Acad Sci U S A. 2019 Oct 17. pii: 1909316116. doi:, 10.1073/pnas.1909316116. PMID:31624125 doi:http://dx.doi.org/10.1073/pnas.1909316116
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