期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1862, 期 12, 页码 2579-2589出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagen.2018.08.007
关键词
DDB-Complex; DDB2; DDB1; Xeroderma Pigmentosum; Molecular dynamics; DNA repair
资金
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul (FAPERGS)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- National Center of Supercomputation (CESUP) of the Universidade Federal do Rio Grande do Sul (UFRGS)
Background: Xeroderma Pigmentosum (XP) is a disease caused by mutations in the nucleotide excision repair (NER) pathway. Patients with XP exhibit a high propensity to skin cancers and some subtypes of XP can even present neurological impairments. During NER, DDB2 (XPE), in complex with DDB1 (DDB-Complex), performs the DNA lesion recognition. However, not much is known about how mutations found in XP patients affect the DDB2 structure and complex assembly. Thus, we searched for structural evidence associated with the role of three naturally occurring mutations found in XPE patients: R273H, K244E, and L350P. Methods: Each mutant was individually constructed and submitted to multiple molecular dynamics simulations, done in triplicate for each designed system. Additionally, Dynamic Residue Interaction Networks were designed for each system and analyzed parallel with the simulations. Results: DDB2 mutations promoted loss of flexibility in the overall protein structure, producing a different conformational behavior in comparison to the WT, especially in the region comprising residues 354 to 371. Furthermore, the DDB-complex containing the mutated forms of DDB2 showed distinct behaviors for each mutant: R273H displayed higher structural instability when complexed; L350P affected DDB1 protein-protein binding with DDB2; and K244E, altered the complex binding trough different ways than L350P. Conclusions: The data gathered throughout the analyses helps to enlighten the structural basis for how naturally occurring mutations found in XPE patients impact on DDB2 and DDB1 function. General significance: Our data influence not only on the knowledge of XP but on the DNA repair mechanisms of NER itself.
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