Phosphopeptide interactions of the Nbs1 N-terminal FHA-BRCT1/2 domains

Abstract Human Nbs1, a component of the MRN complex involved in DNA double strand break repair, contains a concatenated N-terminal FHA-BRCT1/2 sequence that supports interaction with multiple phosphopeptide binding partners. MDC1 binding localizes Nbs1 to the damage site, while binding of CDK-phosph...

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Autores principales:	Kyungmin Kim, Thomas W. Kirby, Lalith Perera, Robert E. London
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/84fb1171b31f475c9785c36d1516f766
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spelling	oai:doaj.org-article:84fb1171b31f475c9785c36d1516f7662021-12-02T13:41:10ZPhosphopeptide interactions of the Nbs1 N-terminal FHA-BRCT1/2 domains10.1038/s41598-021-88400-72045-2322https://doaj.org/article/84fb1171b31f475c9785c36d1516f7662021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88400-7https://doaj.org/toc/2045-2322Abstract Human Nbs1, a component of the MRN complex involved in DNA double strand break repair, contains a concatenated N-terminal FHA-BRCT1/2 sequence that supports interaction with multiple phosphopeptide binding partners. MDC1 binding localizes Nbs1 to the damage site, while binding of CDK-phosphorylated CtIP activates additional ATM-dependent CtIP phosphorylation, modulating substrate-dependent resection. We have investigated the phosphopeptide binding characteristics of Nbs1 BRCT1/2 based on a molecular modeling approach that revealed structural homology with the tandem TopBP1 BRCT7/8 domains. Relevance of the model was substantiated by the ability of TopBP1-binding FANCJ phosphopeptide to interact with hsNbsBRCT1/2, albeit with lower affinity. The modeled BRCT1/2 is characterized by low pSer/pThr selectivity, preference for a cationic residue at the + 2 position, and an inter-domain binding cleft selective for hydrophobic residues at the + 3/ + 4 positions. These features provide insight into the basis for interaction of SDT motifs with the BRCT1/2 domains and allowed identification of CtIP pSer347- and pThr847-containing phosphopeptides as high and lower affinity ligands, respectively. Among other binding partners considered, rodent XRCC1 contains an SDT sequence in the second linker consistent with high-affinity Nbs1 binding, while human XRCC1 lacks this motif, but contains other phosphorylated sequences that exhibit low-affinity binding.Kyungmin KimThomas W. KirbyLalith PereraRobert E. LondonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kyungmin Kim Thomas W. Kirby Lalith Perera Robert E. London Phosphopeptide interactions of the Nbs1 N-terminal FHA-BRCT1/2 domains
description	Abstract Human Nbs1, a component of the MRN complex involved in DNA double strand break repair, contains a concatenated N-terminal FHA-BRCT1/2 sequence that supports interaction with multiple phosphopeptide binding partners. MDC1 binding localizes Nbs1 to the damage site, while binding of CDK-phosphorylated CtIP activates additional ATM-dependent CtIP phosphorylation, modulating substrate-dependent resection. We have investigated the phosphopeptide binding characteristics of Nbs1 BRCT1/2 based on a molecular modeling approach that revealed structural homology with the tandem TopBP1 BRCT7/8 domains. Relevance of the model was substantiated by the ability of TopBP1-binding FANCJ phosphopeptide to interact with hsNbsBRCT1/2, albeit with lower affinity. The modeled BRCT1/2 is characterized by low pSer/pThr selectivity, preference for a cationic residue at the + 2 position, and an inter-domain binding cleft selective for hydrophobic residues at the + 3/ + 4 positions. These features provide insight into the basis for interaction of SDT motifs with the BRCT1/2 domains and allowed identification of CtIP pSer347- and pThr847-containing phosphopeptides as high and lower affinity ligands, respectively. Among other binding partners considered, rodent XRCC1 contains an SDT sequence in the second linker consistent with high-affinity Nbs1 binding, while human XRCC1 lacks this motif, but contains other phosphorylated sequences that exhibit low-affinity binding.
format	article
author	Kyungmin Kim Thomas W. Kirby Lalith Perera Robert E. London
author_facet	Kyungmin Kim Thomas W. Kirby Lalith Perera Robert E. London
author_sort	Kyungmin Kim
title	Phosphopeptide interactions of the Nbs1 N-terminal FHA-BRCT1/2 domains
title_short	Phosphopeptide interactions of the Nbs1 N-terminal FHA-BRCT1/2 domains
title_full	Phosphopeptide interactions of the Nbs1 N-terminal FHA-BRCT1/2 domains
title_fullStr	Phosphopeptide interactions of the Nbs1 N-terminal FHA-BRCT1/2 domains
title_full_unstemmed	Phosphopeptide interactions of the Nbs1 N-terminal FHA-BRCT1/2 domains
title_sort	phosphopeptide interactions of the nbs1 n-terminal fha-brct1/2 domains
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/84fb1171b31f475c9785c36d1516f766
work_keys_str_mv	AT kyungminkim phosphopeptideinteractionsofthenbs1nterminalfhabrct12domains AT thomaswkirby phosphopeptideinteractionsofthenbs1nterminalfhabrct12domains AT lalithperera phosphopeptideinteractionsofthenbs1nterminalfhabrct12domains AT robertelondon phosphopeptideinteractionsofthenbs1nterminalfhabrct12domains
_version_	1718392628926480384

Phosphopeptide interactions of the Nbs1 N-terminal FHA-BRCT1/2 domains

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