9ltp | pdb_00009ltp

Crystal structure of human RAB43 in GDP-AlF3 transition state complex with USP6NL TBC domain

spinqualitylabelsall models 9ltp, resolution 2.49Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9ltp is a 4 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: X-ray diffraction, Resolution 2.49Å Ligands: AF3, GDP, MG, PEG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function US6NL_HUMAN Acts as a GTPase-activating protein for RAB5A and RAB43. Involved in receptor trafficking. In complex with EPS8 inhibits internalization of EGFR. Involved in retrograde transport from the endocytic pathway to the Golgi apparatus. Involved in the transport of Shiga toxin from early and recycling endosomes to the trans-Golgi network. Required for structural integrity of the Golgi complex. Publication Abstract from PubMed TBC domain-containing Rab GTPase-activating proteins (TBCs) play key roles in regulating intracellular trafficking, and mutations in these proteins can disrupt Rab inactivation and contribute to human disease. However, the molecular principles governing the substrate specificity of TBCs remain poorly understood. Here, we delineate the molecular mechanism by which RN-Tre (also known as USP6NL), an RQ-dual finger TBC protein, selectively recognizes and inactivates Rab43. The crystal structure of the RN-Tre-Rab43 complex reveals a bipartite recognition mechanism: the N-terminal subdomain catalytically remodels Rab43 Switch regions, while the C-terminal subdomain engages Switch II and reorients the hydrophobic triad to confer specificity. Structural and mutational analyses identify Leu146 and several C-terminal residues as key determinants of RN-Tre specificity, which lead us to identify Rab19 as an additional substrate. Functional assays demonstrate that disease-associated RN-Tre mutations impair GAP activity, resulting in aberrant Golgi architecture and endocytic trafficking. Collectively, this study establishes a general structural paradigm for substrate discrimination by TBCs and highlights their pivotal roles in membrane trafficking and disease. Molecular basis of Rab43 inactivation by RN-Tre in endocytic trafficking unveils a general Rab-GAP recognition mechanism.,Wang J, Liu T, Zhang Z, Yan W Int J Biol Macromol. 2025 Dec 14;338(Pt 1):149561. doi: , 10.1016/j.ijbiomac.2025.149561. PMID:41401861 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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