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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
eLife Sciences Publications
2013
|
| _version_ | 1797102849432223744 |
|---|---|
| author | Cottee, M Muschalik, N Wong, Y Johnson, C Johnson, S Andreeva, A Oegema, K Lea, S Raff, J Van Breugel, M |
| author_facet | Cottee, M Muschalik, N Wong, Y Johnson, C Johnson, S Andreeva, A Oegema, K Lea, S Raff, J Van Breugel, M |
| author_sort | Cottee, M |
| collection | OXFORD |
| 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. |
| first_indexed | 2024-03-07T06:11:38Z |
| format | Journal article |
| id | oxford-uuid:efb41442-039f-4fae-ab78-cc9714ef3c1e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:11:38Z |
| publishDate | 2013 |
| publisher | eLife Sciences Publications |
| record_format | dspace |
| spelling | oxford-uuid:efb41442-039f-4fae-ab78-cc9714ef3c1e2022-03-27T11:42:11ZCrystal structures of the CPAP/STIL complex reveal its role in centriole assembly and human microcephalyJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:efb41442-039f-4fae-ab78-cc9714ef3c1eEnglishSymplectic Elements at OxfordeLife Sciences Publications2013Cottee, MMuschalik, NWong, YJohnson, CJohnson, SAndreeva, AOegema, KLea, SRaff, JVan Breugel, MCentrioles 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. |
| spellingShingle | Cottee, M Muschalik, N Wong, Y Johnson, C Johnson, S Andreeva, A Oegema, K Lea, S Raff, J Van Breugel, M Crystal structures of the CPAP/STIL complex reveal its role in centriole assembly and human microcephaly |
| title | 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_short | 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 |
| work_keys_str_mv | AT cotteem crystalstructuresofthecpapstilcomplexrevealitsroleincentrioleassemblyandhumanmicrocephaly AT muschalikn crystalstructuresofthecpapstilcomplexrevealitsroleincentrioleassemblyandhumanmicrocephaly AT wongy crystalstructuresofthecpapstilcomplexrevealitsroleincentrioleassemblyandhumanmicrocephaly AT johnsonc crystalstructuresofthecpapstilcomplexrevealitsroleincentrioleassemblyandhumanmicrocephaly AT johnsons crystalstructuresofthecpapstilcomplexrevealitsroleincentrioleassemblyandhumanmicrocephaly AT andreevaa crystalstructuresofthecpapstilcomplexrevealitsroleincentrioleassemblyandhumanmicrocephaly AT oegemak crystalstructuresofthecpapstilcomplexrevealitsroleincentrioleassemblyandhumanmicrocephaly AT leas crystalstructuresofthecpapstilcomplexrevealitsroleincentrioleassemblyandhumanmicrocephaly AT raffj crystalstructuresofthecpapstilcomplexrevealitsroleincentrioleassemblyandhumanmicrocephaly AT vanbreugelm crystalstructuresofthecpapstilcomplexrevealitsroleincentrioleassemblyandhumanmicrocephaly |