PUBLICATION
Structural and functional studies of TBC1D23 C-terminal domain provide a link between endosomal trafficking and PCH
- Authors
- 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.
- ID
- ZDB-PUB-191022-12
- Date
- 2019
- Source
- Proceedings of the National Academy of Sciences of the United States of America 116(45): 22598-22608 (Journal)
- Registered Authors
- Mo, Xianming, Yang, Fan
- Keywords
- Golgi, endosome, membrane trafficking, neuronal development, pontocerebellar hypoplasia
- MeSH Terms
-
- Animals
- Cerebellar Diseases/genetics
- Cerebellar Diseases/metabolism*
- Endosomes/genetics
- Endosomes/metabolism*
- GTPase-Activating Proteins/chemistry*
- GTPase-Activating Proteins/genetics
- GTPase-Activating Proteins/metabolism*
- HeLa Cells
- Humans
- Mutation
- Phosphate-Binding Proteins/chemistry
- Phosphate-Binding Proteins/genetics
- Phosphate-Binding Proteins/metabolism
- Protein Binding
- Protein Domains
- Protein Transport
- Zebrafish
- trans-Golgi Network/genetics
- trans-Golgi Network/metabolism
- PubMed
- 31624125 Full text @ Proc. Natl. Acad. Sci. USA
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. (2019) Structural and functional studies of TBC1D23 C-terminal domain provide a link between endosomal trafficking and PCH. Proceedings of the National Academy of Sciences of the United States of America. 116(45):22598-22608.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping