TY - JOUR
T1 - Structural and functional studies of TBC1D23 C-terminal domain provide a link between endosomal trafficking and PCH
AU - Huang, Wenjie
AU - Liu, Zhe
AU - Yang, Fan
AU - Zhou, Huan
AU - Yong, Xin
AU - Yang, Xiaoyu
AU - Zhou, Yifei
AU - Xue, Lijia
AU - Zhang, Yihong
AU - Liu, Dingdong
AU - Meng, Wentong
AU - Zhang, Wenming
AU - Zhang, Xiaohu
AU - Shen, Xiaofei
AU - Sun, Qingxiang
AU - Li, Li
AU - Ma, Cong
AU - Wei, Yuquan
AU - Billadeau, Daniel D.
AU - Mo, Xianming
AU - Jia, Da
N1 - Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/11/5
Y1 - 2019/11/5
N2 - 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.
AB - 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.
KW - Endosome
KW - Golgi
KW - Membrane trafficking
KW - Neuronal development
KW - Pontocerebellar hypoplasia
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U2 - 10.1073/pnas.1909316116
DO - 10.1073/pnas.1909316116
M3 - Article
C2 - 31624125
AN - SCOPUS:85074517861
SN - 0027-8424
VL - 116
SP - 22598
EP - 22608
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
ER -