Structural and functional studies of TBC1D23 C-terminal domain provide a link between endosomal trafficking and PCH

Wenjie Huang, Zhe Liu, Fan Yang, Huan Zhou, Xin Yong, Xiaoyu Yang, Yifei Zhou, Lijia Xue, Yihong Zhang, Dingdong Liu, Wentong Meng, Wenming Zhang, Xiaohu Zhang, Xiaofei Shen, Qingxiang Sun, Li Li, Cong Ma, Yuquan Wei, Daniel D. Billadeau, Xianming MoDa Jia

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)22598-22608
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number45
StatePublished - Nov 5 2019


  • Endosome
  • Golgi
  • Membrane trafficking
  • Neuronal development
  • Pontocerebellar hypoplasia

ASJC Scopus subject areas

  • General


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