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Crystal structures of the CPAP/STIL complex reveal its role in centriole assembly and human microcephaly

DOI: 10.7554/eLife.01071 DOI Help
PMID: 24052813 PMID Help

Authors: Matthew Cottee (Sir William Dunn School of Pathology, University of Oxford) , Nadine Muschalik (Sir William Dunn School of Pathology, University of Oxford) , Yao Liang Wong (Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California) , Christopher M Johnson (Laboratory of Molecular Biology, Medical Research Council) , Steven Johnson (Sir William Dunn School of Pathology, University of Oxford) , Antonina Andreeva (Laboratory of Molecular Biology, Medical Research Council) , Karen Oegema (Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California) , Susan Lea (Sir William Dunn School of Pathology, University of Oxford) , Jordan W Raff (Sir William Dunn School of Pathology, University of Oxford) , Mark Van Breugel (Laboratory of Molecular Biology, Medical Research Council)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Elife , VOL 2

State: Published (Approved)
Published: September 2013
Diamond Proposal Number(s): 8547

Open Access Open Access

Abstract: Centrioles organise centrosomes and template cilia and flagella. Several centriole and centrosome proteins have been linked to microcephaly (MCPH), a neuro-developmental disease associated with small brain size. CPAP (MCPH6) and STIL (MCPH7) are required for centriole assembly, but it is unclear how mutations in them lead to microcephaly. We show that the TCP domain of CPAP constitutes a novel proline recognition domain that forms a 1:1 complex with a short, highly conserved target motif in STIL. Crystal structures of this complex reveal an unusual, all-β structure adopted by the TCP domain and explain how a microcephaly mutation in CPAP compromises complex formation. Through point mutations, we demonstrate that complex formation is essential for centriole duplication in vivo. Our studies provide the first structural insight into how the malfunction of centriole proteins results in human disease and also reveal that the CPAP–STIL interaction constitutes a conserved key step in centriole biogenesis.

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Documents:
Crystal structures of the CPAPSTIL complex reveal its role in centriole assembly and human microcephaly.pdf

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