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...
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doaj-50efc002b34c4dcdbff8c96256b58ebf2021-05-04T22:31:37ZengeLife Sciences Publications LtdeLife2050-084X2013-09-01210.7554/eLife.01071Crystal structures of the CPAP/STIL complex reveal its role in centriole assembly and human microcephalyMatthew A Cottee0Nadine Muschalik1Yao Liang Wong2Christopher M Johnson3Steven Johnson4Antonina Andreeva5Karen Oegema6Susan M Lea7Jordan W Raff8Mark van Breugel9Sir William Dunn School of Pathology, University of Oxford, Oxford, United KingdomSir William Dunn School of Pathology, University of Oxford, Oxford, United KingdomDepartment of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United StatesLaboratory of Molecular Biology, Medical Research Council, Cambridge, United KingdomSir William Dunn School of Pathology, University of Oxford, Oxford, United KingdomLaboratory of Molecular Biology, Medical Research Council, Cambridge, United KingdomDepartment of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United StatesSir William Dunn School of Pathology, University of Oxford, Oxford, United KingdomSir William Dunn School of Pathology, University of Oxford, Oxford, United KingdomLaboratory of Molecular Biology, Medical Research Council, Cambridge, United KingdomCentrioles 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.https://elifesciences.org/articles/01071centriolecentrosomeCPAPmicrocephalySTIL |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Matthew A Cottee Nadine Muschalik Yao Liang Wong Christopher M Johnson Steven Johnson Antonina Andreeva Karen Oegema Susan M Lea Jordan W Raff Mark van Breugel |
spellingShingle |
Matthew A Cottee Nadine Muschalik Yao Liang Wong Christopher M Johnson Steven Johnson Antonina Andreeva Karen Oegema Susan M Lea Jordan W Raff Mark van Breugel Crystal structures of the CPAP/STIL complex reveal its role in centriole assembly and human microcephaly eLife centriole centrosome CPAP microcephaly STIL |
author_facet |
Matthew A Cottee Nadine Muschalik Yao Liang Wong Christopher M Johnson Steven Johnson Antonina Andreeva Karen Oegema Susan M Lea Jordan W Raff Mark van Breugel |
author_sort |
Matthew A Cottee |
title |
Crystal structures of the CPAP/STIL complex reveal its role in centriole assembly and human microcephaly |
title_short |
Crystal structures of the CPAP/STIL complex reveal its role in centriole assembly and human microcephaly |
title_full |
Crystal structures of the CPAP/STIL complex reveal its role in centriole assembly and human microcephaly |
title_fullStr |
Crystal structures of the CPAP/STIL complex reveal its role in centriole assembly and human microcephaly |
title_full_unstemmed |
Crystal structures of the CPAP/STIL complex reveal its role in centriole assembly and human microcephaly |
title_sort |
crystal structures of the cpap/stil complex reveal its role in centriole assembly and human microcephaly |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2013-09-01 |
description |
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. |
topic |
centriole centrosome CPAP microcephaly STIL |
url |
https://elifesciences.org/articles/01071 |
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