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          Institute: MPI für molekulare Zellbiologie und Genetik     Collection: MPI-CBG Publications 2014 (arch)     Display Documents



ID: 705726.0, MPI für molekulare Zellbiologie und Genetik / MPI-CBG Publications 2014 (arch)
Conserved TCP domain of Sas-4/CPAP is essential for pericentriolar material tethering during centrosome biogenesis.
Authors:Zheng, Xiangdong; Gooi, Li Ming; Wason, Arpit; Gabriel, Elke; Mehrjardi, Narges Zare; Yang, Qian; Zhang, Xingrun; Debec, Alain; Basiri, Marcus L; Avidor-Reiss, Tomer; Pozniakovsky, Andrei I.; Poser, Ina; Saric, Tomo; Hyman, Anthony; Li, Haitao; Gopalakrishnan, Jay
Date of Publication (YYYY-MM-DD):2014
Title of Journal:Proceedings of the National Academy of Sciences of the United States of America
Volume:111
Issue / Number:3
Start Page:354
End Page:363
Copyright:not available
Audience:Experts Only
Intended Educational Use:No
Abstract / Description:Pericentriolar material (PCM) recruitment to centrioles forms a key step in centrosome biogenesis. Deregulation of this process leads to centrosome aberrations causing disorders, one of which is autosomal recessive primary microcephaly (MCPH), a neurodevelopmental disorder where brain size is reduced. During PCM recruitment, the conserved centrosomal protein Sas-4/CPAP/MCPH6, known to play a role in centriole formation, acts as a scaffold for cytoplasmic PCM complexes to bind and then tethers them to centrioles to form functional centrosomes. To understand Sas-4's tethering role, we determined the crystal structure of its T complex protein 10 (TCP) domain displaying a solvent-exposed single-layer of β-sheets fold. This unique feature of the TCP domain suggests that it could provide an "extended surface-like" platform to tether the Sas-4-PCM scaffold to a centriole. Functional studies in Drosophila, human cells, and human induced pluripotent stem cell-derived neural progenitor cells were used to test this hypothesis, where point mutations within the 9-10th β-strands (β9-10 mutants including a MCPH-associated mutation) perturbed PCM tethering while allowing Sas-4/CPAP to scaffold cytoplasmic PCM complexes. Specifically, the Sas-4 β9-10 mutants displayed perturbed interactions with Ana2, a centrosome duplication factor, and Bld-10, a centriole microtubule-binding protein, suggesting a role for the β9-10 surface in mediating protein-protein interactions for efficient Sas-4-PCM scaffold centriole tethering. Hence, we provide possible insights into how centrosomal protein defects result in human MCPH and how Sas-4 proteins act as a vehicle to tether PCM complexes to centrioles independent of its well-known role in centriole duplication.
External Publication Status:published
Document Type:Article
Communicated by:thuem
Affiliations:MPI für molekulare Zellbiologie und Genetik
Identifiers:LOCALID:5631
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