Structural insight into BLM recognition by TopBP1
Topoisomerase IIβ binding protein 1 (TopBP1) is a critical protein-protein interaction hub in DNA replication checkpoint control. It was proposed that TopBP1 BRCT5 interacts with Bloom syndrome helicase (BLM) to regulate genome stability through either phospho-Ser304 or phospho-Ser338 of BLM. Here w...
| Päätekijät: | , , , , , , |
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| Aineistotyyppi: | Journal article |
| Kieli: | English |
| Julkaistu: |
Elsevier
2017
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| _version_ | 1826286689251753984 |
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| author | Sun, L Huang, Y Edwards, R Yang, S Blackford, A Niedzwiedz, W Glover, J |
| author_facet | Sun, L Huang, Y Edwards, R Yang, S Blackford, A Niedzwiedz, W Glover, J |
| author_sort | Sun, L |
| collection | OXFORD |
| description | Topoisomerase IIβ binding protein 1 (TopBP1) is a critical protein-protein interaction hub in DNA replication checkpoint control. It was proposed that TopBP1 BRCT5 interacts with Bloom syndrome helicase (BLM) to regulate genome stability through either phospho-Ser304 or phospho-Ser338 of BLM. Here we show that TopBP1 BRCT5 specifically interacts with the BLM region surrounding pSer304, not pSer338. Our crystal structure of TopBP1 BRCT4/5 bound to BLM reveals recognition of pSer304 by a conserved pSer-binding pocket, and interactions between an FVPP motif N-terminal to pSer304 and a hydrophobic groove on BRCT5. This interaction utilizes the same surface of BRCT5 that recognizes the DNA damage mediator, MDC1; however the binding orientations of MDC1 and BLM are reversed. While the MDC1 interactions are largely electrostatic, the interaction with BLM has higher affinity and relies on a mix of electrostatics and hydrophobicity. We suggest that similar evolutionarily conserved interactions may govern interactions between TopBP1 and 53BP1. |
| first_indexed | 2024-03-07T01:47:28Z |
| format | Journal article |
| id | oxford-uuid:98eb4374-f2f0-4dbf-a9fc-c5404d690c46 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:47:28Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:98eb4374-f2f0-4dbf-a9fc-c5404d690c462022-03-27T00:10:30ZStructural insight into BLM recognition by TopBP1Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:98eb4374-f2f0-4dbf-a9fc-c5404d690c46EnglishSymplectic Elements at OxfordElsevier2017Sun, LHuang, YEdwards, RYang, SBlackford, ANiedzwiedz, WGlover, JTopoisomerase IIβ binding protein 1 (TopBP1) is a critical protein-protein interaction hub in DNA replication checkpoint control. It was proposed that TopBP1 BRCT5 interacts with Bloom syndrome helicase (BLM) to regulate genome stability through either phospho-Ser304 or phospho-Ser338 of BLM. Here we show that TopBP1 BRCT5 specifically interacts with the BLM region surrounding pSer304, not pSer338. Our crystal structure of TopBP1 BRCT4/5 bound to BLM reveals recognition of pSer304 by a conserved pSer-binding pocket, and interactions between an FVPP motif N-terminal to pSer304 and a hydrophobic groove on BRCT5. This interaction utilizes the same surface of BRCT5 that recognizes the DNA damage mediator, MDC1; however the binding orientations of MDC1 and BLM are reversed. While the MDC1 interactions are largely electrostatic, the interaction with BLM has higher affinity and relies on a mix of electrostatics and hydrophobicity. We suggest that similar evolutionarily conserved interactions may govern interactions between TopBP1 and 53BP1. |
| spellingShingle | Sun, L Huang, Y Edwards, R Yang, S Blackford, A Niedzwiedz, W Glover, J Structural insight into BLM recognition by TopBP1 |
| title | Structural insight into BLM recognition by TopBP1 |
| title_full | Structural insight into BLM recognition by TopBP1 |
| title_fullStr | Structural insight into BLM recognition by TopBP1 |
| title_full_unstemmed | Structural insight into BLM recognition by TopBP1 |
| title_short | Structural insight into BLM recognition by TopBP1 |
| title_sort | structural insight into blm recognition by topbp1 |
| work_keys_str_mv | AT sunl structuralinsightintoblmrecognitionbytopbp1 AT huangy structuralinsightintoblmrecognitionbytopbp1 AT edwardsr structuralinsightintoblmrecognitionbytopbp1 AT yangs structuralinsightintoblmrecognitionbytopbp1 AT blackforda structuralinsightintoblmrecognitionbytopbp1 AT niedzwiedzw structuralinsightintoblmrecognitionbytopbp1 AT gloverj structuralinsightintoblmrecognitionbytopbp1 |