Nuclear localization of the DNA repair scaffold XRCC1: Uncovering the functional role of a bipartite NLS

Kirby, Thomas W.; Gassman, Natalie R.; Smith, Cassandra E.; Pedersen, Lars C.; Gabel, Scott A.; Sobhany, Mack; Wilson, Samuel H.; London, Robert E.

doi:10.1038/srep13405

Nuclear localization of the DNA repair scaffold XRCC1: Uncovering the functional role of a bipartite NLS

Journal Article · Tue Aug 25 00:00:00 EDT 2015 · Scientific Reports

DOI:https://doi.org/10.1038/srep13405· OSTI ID:1213717

Kirby, Thomas W. ^[1]; Gassman, Natalie R. ^[1]; Smith, Cassandra E. ^[1]; Pedersen, Lars C. ^[1]; Gabel, Scott A. ^[1]; Sobhany, Mack ^[1]; Wilson, Samuel H. ^[1]; London, Robert E. ^[1]

National Inst. of Health (NIH), Research Triangle Park, NC (United States)

We have characterized the nuclear localization signal (NLS) of XRCC1 structurally using X-ray crystallography and functionally using fluorescence imaging. Crystallography and binding studies confirm the bipartite nature of the XRCC1 NLS interaction with Importin α (Impα) in which the major and minor binding motifs are separated by >20 residues, and resolve previous inconsistent determinations. Binding studies of peptides corresponding to the bipartite NLS, as well as its major and minor binding motifs, to both wild-type and mutated forms of Impα reveal pronounced cooperative binding behavior that is generated by the proximity effect of the tethered major and minor motifs of the NLS. The cooperativity stems from the increased local concentration of the second motif near its cognate binding site that is a consequence of the stepwise binding behavior of the bipartite NLS. We predict that the stepwise dissociation of the NLS from Impα facilitates unloading by providing a partially complexed intermediate that is available for competitive binding by Nup50 or the Importin β binding domain. This behavior gives a basis for meeting the intrinsically conflicting high affinity and high flux requirements of an efficient nuclear transport system.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357; W-31109-ENG-38

OSTI ID:: 1213717

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Vol. 5; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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