Dataset Information

Conformational determinants for the recruitment of ERCC1 by XPA in the nucleotide excision repair (NER) Pathway: structure and dynamics of the XPA binding motif.

ABSTRACT: XPA is an essential protein in the nucleotide excision repair (NER) pathway, in charge of recruiting the ERCC1-XPF endonuclease complex to the DNA damage site. The only currently available structural insight into the binding of XPA to ERCC1 derives from the solution NMR structure of a complex between the ERCC1 central fragment and a 14-residue peptide, corresponding to the highly conserved binding motif of the XPA N-terminus, XPA?????. The extensive all-atom molecular-dynamics simulation study of the XPA????? peptide both bound to the ERCC1 central fragment and free in solution presented here completes the profile of the structural determinants responsible for the ERCC1/XPA????? complex stability. In addition to the wild-type, this study also looks at specific XPA????? mutants in complex with the ERCC1 central domain and thus contributes to defining the conformational determinants for binding, as well as all of the essential structural elements necessary for the rational design of an XPA-based, ERCC1-specific inhibitor.

SUBMITTER: Fadda E

PROVIDER: S-EPMC3672865 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Publications

Conformational determinants for the recruitment of ERCC1 by XPA in the nucleotide excision repair (NER) Pathway: structure and dynamics of the XPA binding motif.

Fadda Elisa E

Biophysical journal 20130601 11

XPA is an essential protein in the nucleotide excision repair (NER) pathway, in charge of recruiting the ERCC1-XPF endonuclease complex to the DNA damage site. The only currently available structural insight into the binding of XPA to ERCC1 derives from the solution NMR structure of a complex between the ERCC1 central fragment and a 14-residue peptide, corresponding to the highly conserved binding motif of the XPA N-terminus, XPA₆₇₋₈₀. The extensive all-atom molecular-dynamics simulation study o ...[more]

PMID: 23746523

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Project description:Nucleotide excision repair (NER) is a pivotal life process for repairing DNA nucleotide mismatch caused by chemicals, metal ions, radiation, and other factors. As the initiation step of NER, the xeroderma pigmentosum complementation group A protein (XPA) recognizes damaged DNA molecules, and recruits the replication protein A (RPA), another important player in the NER process. The stability of the Zn(2+)-chelated Zn-finger domain of XPA center core portion (i.e., XPA98-210) is the foundation of its biological functionality, while the displacement of the Zn(2+) by toxic metal ions (such as Ni(2+), a known human carcinogen and allergen) may impair the effectiveness of NER and hence elevate the chance of carcinogenesis. In this study, we first calculated the force field parameters for the bonded model in the metal center of the XPA98-210 system, showing that the calculated results, including charges, bonds, angles etc., are congruent with previously reported results measured by spectrometry experiments and quantum chemistry computation. Then, comparative molecular dynamics simulations using these parameters revealed the changes in the conformation and motion mode of XPA98-210 Zn-finger after the substitution of Zn(2+) by Ni(2+). The results showed that Ni(2+) dramatically disrupted the relative positions of the four Cys residues in the Zn-finger structure, forcing them to collapse from a tetrahedron into an almost planar structure. Finally, we acquired the binding mode of XPA98-210 with its ligands RPA70N and DNA based on molecular docking and structural alignment. We found that XPA98-210's Zn-finger domain primarily binds to a V-shaped cleft in RPA70N, while the cationic band in its C-terminal subdomain participates in the recognition of damaged DNA. In addition, this article sheds light on the multi-component interaction pattern among XPA, DNA, and other NER-related proteins (i.e., RPA70N, RPA70A, RPA70B, RPA70C, RPA32, and RPA14) based on previously reported structural biology information. Thus, we derived a putative cytotoxic mechanism associated with the nickel ion, where the Ni(2+) disrupts the conformation of the XPA Zn-finger, directly weakening its interaction with RPA70N, and thus lowering the effectiveness of the NER process. In sum, this work not only provides a theoretical insight into the multi-protein interactions involved in the NER process and potential cytotoxic mechanism associated with Ni(2+) binding in XPA, but may also facilitate rational anti-cancer drug design based on the NER mechanism.

Dataset Information

Conformational determinants for the recruitment of ERCC1 by XPA in the nucleotide excision repair (NER) Pathway: structure and dynamics of the XPA binding motif.

Publications

Conformational determinants for the recruitment of ERCC1 by XPA in the nucleotide excision repair (NER) Pathway: structure and dynamics of the XPA binding motif.

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