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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. DOI:http://dx.doi.org/10.7554/eLife.01071.001.
Highlights
Centrioles are small cylindrical organelles whose outer walls contain a ninefold symmetric array of microtubule triplets
The CPAP TCP domain binds to a conserved proline-rich motif in STIL
To try to identify the region of STIL most likely to be involved in an interaction with CPAP, we carried out a sequence alignment with multiple metazoan STIL proteins (Figure 1A, Figure 1—figure supplement 1)
Summary
Centrioles are small cylindrical organelles whose outer walls contain a ninefold symmetric array of microtubule triplets These structures form the basal bodies that template the assembly of cilia and flagella, and they organise a proteinaceous matrix termed the pericentriolar material (PCM) to form centrosomes, the main microtubule organising centres in animal cells. All eight identified MCPH genes encode proteins that localise to centrioles and/or centrosomes/spindle poles (Thornton and Woods, 2009; Hussain et al, 2012) It is unclear why mutations in these proteins are linked to such a specific neurodevelopmental problem in humans, but it seems likely that some aspect of centriole/centrosome function must be important for the proper proliferation of human neural progenitors (Siller and Doe, 2009; Megraw et al, 2011).
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