Role of the XPA protein in the NER pathway: a perspective on the function of structural disorder in macromolecular assembly
Role of the XPA protein in the NER pathway: a perspective on the function of structural disorder in macromolecular assembly
Lack of structure is often an essential functional feature of protein domains. The coordination of macromolecular assemblies in DNA repair pathways is yet another task disordered protein regions are highly implicated in. Here I review the available experimental and computational data and within this context discuss the functional role of structure and disorder in one of the essential scaffolding proteins in the nucleotide excision repair (NER) pathway, namely Xeroderma pigmentosum complementation group A (XPA). From the analysis of the current knowledge, in addition to protein-protein docking and secondary structure prediction results presented for the first time herein, a mechanistic framework emerges, where XPA builds the NER pre-incision complex in a modular fashion, as "beads on a string", where the protein-protein interaction "beads", or modules, are interconnected by disordered link regions. This architecture is ideal to avoid the expected steric hindrance constraints of the DNA expanded bubble. Finally, the role of the XPA structural disorder in binding affinity modulation and in the sequential binding of NER core factors in the pre-incision complex is also discussed.
Beads-on-a-string multiprotein complex, Conformational selection, ERCC1-XPF, Molecular recognition, NER pre-incision complex, Nucleotide Excision Repair (XPA), RPA, Structurally disordered protein domains, XPA
78-85
Fadda, Elisa
11ba1755-9585-44aa-a38e-a8bcfd766abb
29 December 2015
Fadda, Elisa
11ba1755-9585-44aa-a38e-a8bcfd766abb
Fadda, Elisa
(2015)
Role of the XPA protein in the NER pathway: a perspective on the function of structural disorder in macromolecular assembly.
Computational and Structural Biotechnology Journal, 14, .
(doi:10.1016/j.csbj.2015.11.007).
Abstract
Lack of structure is often an essential functional feature of protein domains. The coordination of macromolecular assemblies in DNA repair pathways is yet another task disordered protein regions are highly implicated in. Here I review the available experimental and computational data and within this context discuss the functional role of structure and disorder in one of the essential scaffolding proteins in the nucleotide excision repair (NER) pathway, namely Xeroderma pigmentosum complementation group A (XPA). From the analysis of the current knowledge, in addition to protein-protein docking and secondary structure prediction results presented for the first time herein, a mechanistic framework emerges, where XPA builds the NER pre-incision complex in a modular fashion, as "beads on a string", where the protein-protein interaction "beads", or modules, are interconnected by disordered link regions. This architecture is ideal to avoid the expected steric hindrance constraints of the DNA expanded bubble. Finally, the role of the XPA structural disorder in binding affinity modulation and in the sequential binding of NER core factors in the pre-incision complex is also discussed.
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Accepted/In Press date: 26 November 2015
e-pub ahead of print date: 8 December 2015
Published date: 29 December 2015
Keywords:
Beads-on-a-string multiprotein complex, Conformational selection, ERCC1-XPF, Molecular recognition, NER pre-incision complex, Nucleotide Excision Repair (XPA), RPA, Structurally disordered protein domains, XPA
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Local EPrints ID: 499800
URI: http://eprints.soton.ac.uk/id/eprint/499800
ISSN: 2001-0370
PURE UUID: e4636267-1e7d-4a90-807f-0761620fb6a8
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Date deposited: 04 Apr 2025 16:41
Last modified: 22 Aug 2025 02:42
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Author:
Elisa Fadda
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