CCDC61/VFL3 Is a Paralog of SAS6 and Promotes Ciliary Functions

Structure. 2020 Jun 2;28(6):674-689.e11. doi: 10.1016/j.str.2020.04.010.

Takashi Ochi ¹, Valentina Quarantotti ², Huawen Lin ³, Jerome Jullien ⁴, Ivan Rosa E Silva ⁵, Francesco Boselli ⁶, Deepak D Barnabas ⁵, Christopher M Johnson ⁵, Stephen H McLaughlin ⁵, Stefan M V Freund ⁵, Andrew N Blackford ⁷, Yuu Kimata ⁸, Raymond E Goldstein ⁶, Stephen P Jackson ⁹, Tom L Blundell ¹⁰, Susan K Dutcher ³, Fanni Gergely ², Mark van Breugel ¹¹

Affiliations

1 MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address: T.Ochi@leeds.ac.uk.
2 Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
3 Department of Genetics, Washington University School of Medicine, 4523 Clayton Avenue, St Louis, MO 63110, USA.
4 Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK; Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK; CRTI, INSERM, UNIV Nantes, Nantes, France.
5 MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
6 DAMTP, Centre for Mathematical Sciences, Wilberforce Road, Cambridge CB3 0WA, UK.
7 Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
8 Department of Genetics, University of Cambridge, Cambridge CB4 1AR, UK; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
9 Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
10 Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
11 MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address: m.vanbreugel@qmul.ac.uk.

PMID: 32375023 DOI: 10.1016/j.str.2020.04.010

Abstract

Centrioles are cylindrical assemblies whose peripheral microtubule array displays a 9-fold rotational symmetry that is established by the scaffolding protein SAS6. Centriole symmetry can be broken by centriole-associated structures, such as the striated fibers in Chlamydomonas that are important for ciliary function. The conserved protein CCDC61/VFL3 is involved in this process, but its exact role is unclear. Here, we show that CCDC61 is a paralog of SAS6. Crystal structures of CCDC61 demonstrate that it contains two homodimerization interfaces that are similar to those found in SAS6, but result in the formation of linear filaments rather than rings. Furthermore, we show that CCDC61 binds microtubules and that residues involved in CCDC61 microtubule binding are important for ciliary function in Chlamydomonas. Together, our findings suggest that CCDC61 and SAS6 functionally diverged from a common ancestor while retaining the ability to scaffold the assembly of basal body-associated structures or centrioles, respectively.

Keywords

CCDC61; Chlamydomonas; SAS6; VFL3; XRCC4; basal body; centriole; centrosome; cilia; microtubule; structural biology.

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