8jj9 | pdb_00008jj9
Human FAM91A1 N terminal domain in complex with TBC1D23
Structural highlights
DiseaseTBC23_HUMAN The disease is caused by mutations affecting the gene represented in this entry. FunctionTBC23_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 PubMedPontocerebellar hypoplasia (PCH) is a group of rare neurodevelopmental disorders with limited diagnostic and therapeutic options. Mutations in WDR11, a subunit of the FAM91A1 complex, have been found in patients with PCH-like symptoms; however, definitive evidence that the mutations are causal is still lacking. Here, we show that depletion of FAM91A1 results in developmental defects in zebrafish similar to that of TBC1D23, an established PCH gene. FAM91A1 and TBC1D23 directly interact with each other and cooperate to regulate endosome-to-Golgi trafficking of KIAA0319L, a protein known to regulate axonal growth. Crystal structure of the FAM91A1-TBC1D23 complex reveals that TBC1D23 binds to a conserved surface on FAM91A1 by assuming a Z-shaped conformation. More importantly, the interaction between FAM91A1 and TBC1D23 can be used to predict the risk of certain TBC1D23-associated mutations to PCH. Collectively, our study provides a molecular basis for the interaction between TBC1D23 and FAM91A1 and suggests that disrupted endosomal trafficking underlies multiple PCH subtypes. FAM91A1-TBC1D23 complex structure reveals human genetic variations susceptible for PCH.,Zhao L, Deng H, Yang Q, Tang Y, Zhao J, Li P, Zhang S, Yong X, Li T, Billadeau DD, Jia D Proc Natl Acad Sci U S A. 2023 Nov 7;120(45):e2309910120. doi: , 10.1073/pnas.2309910120. Epub 2023 Oct 30. PMID:37903274[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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