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Protein-protein interactions involved in copper homeostasis, oxidative aging and neurodegenerative disease

Grant number: 15/00062-1
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): May 01, 2015
Effective date (End): March 31, 2020
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Richard Charles Garratt
Grantee:Fernanda Angélica Sala
Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Associated scholarship(s):16/24686-7 - Protein-protein interactions involved in copper homeostasis., BE.EP.DR


Superoxide dismutase-1 (SOD1) is a ubiquitous and highly expressed antioxidant metalloprotein that catalyses the dismutation of superoxide anion to hydrogen peroxide and oxygen by redox cycling of copper. Even after the first reports of SOD1, for over forty years, and the knowledge of its importance in cellular processes, little is understood about its maturation mechanism. Studies emphasize the importance of chaperon proteins for SOD1 (hCCs) that specifically recognizes the SOD1 newly translated, and active them by inserting a catalytic copper ion and by the oxidation of the disulfide bond, generating a SOD1 homodimer mature and stable. Mutations in the gene encoding SOD1 are associated with Amyotrophic Lateral Sclerosis (ALS), however little is known about how these mutations may interfere in metal incorporation into protein, in the oxidation of disulfide bond, and or interaction with hCCs. Studies involving obtaining crystallographic structures of hCCS-SOD1 complex are challenging, because the entire hCCs protein has been described as difficult to crystallization. A combination of mutant ALS is considered more crystallizable than the native form. Thus, this project aims to describe the mechanism by which hCCs imparts both activity and stability upon SOD1 and discover the cause of its misfunction in case of ALS. SEC-SAXS / DLS / SLS will be employed to enhance the targets and find out how the mutants affect the shape and conformational dynamics of the complex. The complexes that shows better results will be conducted for crystallization trials. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LEONARDO, DIEGO A.; CAVINI, ITALO A.; SALA, FERNANDA A.; MENDONCA, DEBORAH C.; ROSA, HIGOR V. D.; KUMAGAI, PATRICIA S.; CRUSCA JR, EDSON; VALADARES, NAPOLEAO F.; MARQUES, IVO A.; BRANDAO-NETO, JOSE; et al. Orientational Ambiguity in Septin Coiled Coils and its Structural Basis. Journal of Molecular Biology, v. 433, n. 9, . (18/20209-5, 16/04658-9, 17/07709-6, 19/22000-9, 14/15546-1, 15/00062-1, 13/04433-9, 15/16811-3, 18/19992-7)
SALA, FERNANDA A.; WRIGHT, GARETH S. A.; ANTONYUK, V, SVETLANA; GARRATT, RICHARD C.; HASNAIN, S. SAMAR. Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS. PLOS BIOLOGY, v. 17, n. 2, . (15/00062-1, 16/24686-7)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
SALA, Fernanda Angélica. Protein-protein interactions involved in copper homeostasis, oxidative aging and neurodegenerative disease. 2020. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Química de São Carlos (IQSC/BT) São Carlos.

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