Journal
ELIFE
Volume 2, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.01071
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Categories
Funding
- UK Medical Research Council [MC_UP_1201/3, G0900888]
- Cancer Research UK [10530]
- Wellcome Trust [083599/Z/07/Z]
- National Institutes of Health [R01-GM074207]
- Ludwig Institute for Cancer Research
- Biotechnology and Biological Sciences Research Council UK
- Biotechnology and Biological Sciences Research Council [984451] Funding Source: researchfish
- Medical Research Council [MC_U105192716, MC_UP_1201/3] Funding Source: researchfish
- MRC [MC_U105192716, MC_UP_1201/3] Funding Source: UKRI
- Wellcome Trust [083599/Z/07/Z] Funding Source: Wellcome Trust
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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-beta 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.
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