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Title: Structural modeling and analyses of genetic variations in the human XPC nucleotide excision repair protein
Xeroderma pigmentosum C (XPC) is a key initiator in the global genome nucleotide excision repair pathway in mammalian cells. Inherited mutations in the XPC gene can cause xeroderma pigmentosum (XP) cancer predisposition syndrome that dramatically increases the susceptibility to sunlight-induced cancers. Various genetic variants and mutations of the protein have been reported in cancer databases and literature. The current lack of a high-resolution 3-D structure of human XPC makes it difficult to assess the structural impact of the mutations/genetic variations. Using the available high-resolution crystal structure of its yeast ortholog, Rad4, we built a homology model of human XPC protein and compared it with a model generated by AlphaFold. The two models are largely consistent with each other in the structured domains. We have also assessed the degree of conservation for each residue using 966 sequences of XPC orthologs. Our structure- and sequence conservation-based assessments largely agree with the variant’s impact on the protein’s structural stability, computed by FoldX and SDM. Known XP missense mutations such as Y585C, W690S, and C771Y are consistently predicted to destabilize the protein’s structure. Our analyses also reveal several highly conserved hydrophobic regions that are surface-exposed, which may indicate novel intermolecular interfaces that are yet to be characterized.  more » « less
Award ID(s):
2131806
PAR ID:
10519476
Author(s) / Creator(s):
;
Publisher / Repository:
Taylor and Francis
Date Published:
Journal Name:
Journal of Biomolecular Structure and Dynamics
Volume:
41
Issue:
23
ISSN:
0739-1102
Page Range / eLocation ID:
13535 to 13562
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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