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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Role of a high centrality residue in protein dynamics and thermal stability

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Almeida, Vitor Medeiros [1] ; Chaudhuri, Apala [2] ; Cardoso, Marcus Vinicius Cangussu [3] ; Matsuyama, Bruno Yasui [1] ; Ferreira, Glaucio Monteiro [4] ; Goulart Trossini, Gustavo Henrique [4] ; Salinas, Roberto Kopke [1] ; Loria, J. Patrick [2, 5] ; Marana, Sandro Roberto [1]
Total Authors: 9
[1] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo, SP - Brazil
[2] Yale Univ, Dept Chem, New Haven, CT - USA
[3] Univ Fed Ouro Preto, Inst Ciencias Exatas & Biol, Dept Quim, Ouro Preto, MG - Brazil
[4] Univ Sao Paulo, Sch Pharmaceut Sci, Sao Paulo, SP - Brazil
[5] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT - USA
Total Affiliations: 5
Document type: Journal article
Source: Journal of Structural Biology; v. 213, n. 3 SEP 2021.
Web of Science Citations: 0

Centralities determined from Residue Interaction Networks (RIN) in proteins have been used to predict aspects of their structure and dynamics. Here, we correlate the Eigenvector Centrality (E-c) with the rate constant for thermal denaturation (k(den)) of the HisF protein from Thermotoga maritima based on 12 single alanine substitution mutants. The molecular basis for this correlation was further explored by studying a mutant containing a replacement of a high E-c residue, Y182A, which displayed increased k(den) at 80 degrees C. The crystallographic structure of this mutant showed few changes, mostly in two flexible loops. The H-1-N-15-HSQC showed only subtle changes of cross peak positions for residues located near the mutation site and scattered throughout the structure. However, the comparison of the RIN showed that Y182 is the vertex of a set of high centrality residues that spreads throughout the HisF structure, which is lacking in the mutant. Cross-correlation displacements of C alpha calculated from a molecular dynamics simulation at different temperatures showed that the Y182A mutation reduced the correlated movements in the HisF structure above 70 degrees C. H-1-N-15 NMR chemical shift covariance using temperature as perturbation were consistent with these results. In conclusion the increase in temperature drives the structure of the mutant HisF-Y182A into a less connected state, richer in non-concerted motions, located predominantly in the C-terminal half of the protein where Y182 is placed. Conversely, wild-type HisF responds to increased temperature as a single unit. Hence the replacement of a high E-c residue alters the distribution of thermal energy through HisF structure. (AU)

FAPESP's process: 19/24112-9 - Novel HMG-CoA reductase inhibitors development by integrating dyslipidemic patients' genetic studies and molecular modelling
Grantee:Glaucio Monteiro Ferreira
Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
FAPESP's process: 17/25543-8 - Medicinal Chemistry strategies (LBDD and SBDD) in the search of tripanomatides sirtuin 2 inhibitors
Grantee:Gustavo Henrique Goulart Trossini
Support Opportunities: Regular Research Grants
FAPESP's process: 18/25952-8 - Catalysis and Thermostability in Enzymes: Oligomerization, Structure Network and Dynamics Effects
Grantee:Sandro Roberto Marana
Support Opportunities: Regular Research Grants
FAPESP's process: 16/12899-6 - Genomics, epigenomics and pharmacogenomics characterization of familial hypercholesterolemia in the Brazilian population
Grantee:Mario Hiroyuki Hirata
Support Opportunities: Research Projects - Thematic Grants