Substrate-dependent millisecond domain motions in DNA polymerase β
Identifieur interne : 001D07 ( Main/Exploration ); précédent : 001D06; suivant : 001D08Substrate-dependent millisecond domain motions in DNA polymerase β
Auteurs : Rebecca B. Berlow [États-Unis] ; Monalisa Swain [États-Unis] ; Shibani Dalal [États-Unis] ; Joann B. Sweasy [États-Unis] ; J. Patrick Loria [États-Unis]Source :
- Journal of Molecular Biology [ 0022-2836 ] ; 2012.
Abstract
DNA polymerase β (Pol β) is a 39 kDa enzyme that performs the vital cellular function of repairing damaged DNA. Mutations in Pol β have been linked to various cancers and these mutations further correlated with altered Pol β enzymatic activity. The fidelity of correct nucleotide incorporation into damaged DNA is essential for Pol β repair function and several studies have implicated conformational changes in Pol β as a determinant of this repair fidelity. In this work, the rate constants for domain motions in Pol β have been determined by solution NMR relaxation dispersion for the apo and substrate, binary forms of Pol β. In apo Pol β, molecular motions, primarily isolated to the DNA lyase domain, are observed to occur at 1400 s–1. Additional analysis suggests that these motions allow apo Pol β to sample a conformation similar to the gapped, DNA substrate bound form. Upon binding DNA, these lyase domain motions are significantly quenched whereas evidence for conformational motions in the polymerase domain become apparent. These NMR studies suggest an alteration in the dynamic landscape of Pol β due to substrate binding. Moreover, a number of the flexible residues identified in this work are also the location of residues, which upon mutation, lead to cancer phenotypes
Url:
DOI: 10.1016/j.jmb.2012.03.013
PubMed: 22446382
PubMed Central: 3348416
Affiliations:
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Le document en format XML
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<front><div type="abstract" xml:lang="en"><p id="P2">DNA polymerase β (Pol β) is a 39 kDa enzyme that performs the vital cellular function of repairing damaged DNA. Mutations in Pol β have been linked to various cancers and these mutations further correlated with altered Pol β enzymatic activity. The fidelity of correct nucleotide incorporation into damaged DNA is essential for Pol β repair function and several studies have implicated conformational changes in Pol β as a determinant of this repair fidelity. In this work, the rate constants for domain motions in Pol β have been determined by solution NMR relaxation dispersion for the apo and substrate, binary forms of Pol β. In apo Pol β, molecular motions, primarily isolated to the DNA lyase domain, are observed to occur at 1400 s<sup>–1</sup>
. Additional analysis suggests that these motions allow apo Pol β to sample a conformation similar to the gapped, DNA substrate bound form. Upon binding DNA, these lyase domain motions are significantly quenched whereas evidence for conformational motions in the polymerase domain become apparent. These NMR studies suggest an alteration in the dynamic landscape of Pol β due to substrate binding. Moreover, a number of the flexible residues identified in this work are also the location of residues, which upon mutation, lead to cancer phenotypes <italic>in vivo</italic>
, which may be due to the intimate role of protein motions in Pol β fidelity.</p>
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