Crystal structures of the CPAP/STIL complex reveal its role in centriole assembly and human microcephaly.
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.
Sir William Dunn School of Pathology , University of Oxford , Oxford , United Kingdom.
Matthew A
MA
Cottee
Nadine
N
Muschalik
Yao Liang
YL
Wong
Christopher M
CM
Johnson
Steven
S
Johnson
Antonina
A
Andreeva
Karen
K
Oegema
Susan M
SM
Lea
Jordan W
JW
Raff
Mark
M
van Breugel
D001665:Binding Sites; D002502:Centrioles; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000502:physiology; D008831:Microcephaly / Q000503:physiopathology*; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000502:physiology; D017354:Point Mutation; D011392:Proline / Q000737:chemistry; D011487:Protein Conformation
C414735:CENPJ protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; C071236:STIL protein, human; D011392:Proline
C. elegans; CPAP; D. melanogaster; STIL; Zebrafish; centriole; centrosome; microcephaly