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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.)

HsDHODH Microdomain-Membrane Interactions Influenced by the Lipid Composition

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Author(s):
Vicente, Eduardo F. [1] ; Sahu, Indra D. [2] ; Crusca, Jr., Edson [3, 4] ; Basso, Luis G. M. [5] ; Munte, Claudia E. [3] ; Costa-Filho, Antonio J. [5] ; Lorigan, Gary A. [2] ; Cilli, Eduardo M. [4]
Total Authors: 8
Affiliation:
[1] Sao Paulo State Univ UNESP, Sch Sci & Engn, BR-17602496 Tupa, SP - Brazil
[2] Miami Univ, Dept Chem & Biochem, Oxford, OH 45056 - USA
[3] Univ Sao Paulo, Inst Fis Sao Carlos, BR-13566590 Sao Carlos, SP - Brazil
[4] Sao Paulo State Univ UNESP, Inst Chem, BR-14800900 Araraquara, SP - Brazil
[5] Univ Sao Paulo, Fac Filosofia Ciencias & Letras Ribeirao Preto, Dept Fis, Lab Biofis Mol, BR-14040901 Ribeirao Preto, SP - Brazil
Total Affiliations: 5
Document type: Journal article
Source: Journal of Physical Chemistry B; v. 121, n. 49, p. 11085-11095, DEC 14 2017.
Web of Science Citations: 1
Abstract

Human dihydroorotate dehydrogenase (HsDHODH) enzyme has been studied as selective target for inhibitors to block the enzyme activity, intending to prevent proliferative diseases. The N-terminal microdomain seems to play an important role in the enzyme function. However, the molecular mechanism of action and dynamics of this region are not totally understood yet. This study analyzes the interaction and conformation in model membranes of HsDHODH microdothain using peptide, analogues containing the paramagnetic amino acid TOAC at strategic positions. In buffer solution, the analogues presented a disordered conformation, but acquired a high content of alpha-helical structure in membrane mimetics, which was found to be lipid dependent. The microdomain peptide structure in micelles showed a very different peptide conformation when compared to the reported crystal structure, displaying a conformational flexibility of its helices, promoted by the connecting loop, which might be functionally relevant. Electron spin resonance in membrane compositions containing POPC, POPE, and cardiolipin showed that interaction of the analogues was enhanced by the presence of cardiolipin, indicating that the microdomain preferentially interacts with cardiolipin-containing membranes. Therefore, the great flexibility of the microdomain and the cardiolipin affinity should be considered in further studies aimed at finding new inhibitory compounds to fight proliferative diseases. (AU)

FAPESP's process: 10/12953-4 - Structural determination of the C-terminal domains of septins SEPT2 and SEPT4 and protein interaction with alpha-synuclein by NMR
Grantee:Edson Crusca Junior
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 14/00206-0 - Structure and function of SARS-CoV spike glycoprotein fusion peptides
Grantee:Luís Guilherme Mansor Basso
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 10/06526-6 - Synthetic Peptides in DHODH and fusion peptide Dengue virus studies.
Grantee:Eduardo Maffud Cilli
Support Opportunities: Regular Research Grants
FAPESP's process: 15/18390-5 - Electron magnetic resonance in molecular biophysics: new and old looks to new and old problems
Grantee:Antonio José da Costa Filho
Support Opportunities: Regular Research Grants