6JM5

Crystal structure of TBC1D23 C terminal domain

Summary for 6JM5

• Entry DOI: 10.2210/pdb6jm5/pdb
• Descriptor: TBC1 domain family member 23, SODIUM ION (3 entities in total)
• Functional Keywords: membrane fusion, bridging factor, endosomal tranport, protein transport
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 27811.43

Authors

Sun, Q.,Huang, W. (deposition date: 2019-03-07, release date: 2019-10-16, Last modification date: 2024-03-27)

Primary citation

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, D.D.,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.USA, 116:22598-22608, 2019

PubMed Abstract: 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.

PubMed: 31624125
DOI: 10.1073/pnas.1909316116

Experimental method

X-RAY DIFFRACTION (1.6 Å)