Protein-protein interactions involved in copper homeostasis.

• Grant number: 16/24686-7
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: May 01, 2017
• End date: April 30, 2018
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Richard Charles Garratt
• Grantee: Fernanda Angélica Sala
• Supervisor: Samar Hasnain
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Institution abroad: University of Liverpool, England
• Associated to the scholarship: 15/00062-1 - Protein-protein interactions involved in copper homeostasis, oxidative aging and neurodegenerative disease, BP.DR

Abstract

The redox metal copper is an essential cofactor for a number of enzymes that have critical roles in biological processes, including the bimetallic Cu, Zn-Superoxide dismutase (SOD1). As it is highly toxic when allowed to accumulate, its bioavailability is tightly regulated involving transporters and chaperones to ensure Cu homeostasis and maintain intracellular free copper concentration at minimum levels. The integral membrane transporter (CTR-1) has recently been identified and is thought to play a central role in importing copper into eukaryotic cells in the form of Cu(I) and provide this essential metal to a number of metallochaperones including hCCS (copper chaperone for SOD1). However, to date, it is unclear how the chaperones acquire their cargo. It has been hypothesized that metal transfer occurs via direct protein-protein interaction between CTR1 and metallochaperones. Thus, the objective of this project is to study the interaction and copper transfer mechanism from CTR1 to hCCS and finally to SOD1 under physiological conditions. Our ultimate aim is to establish the nature of binary (CTR1-hCCS) and ternary (CTR1-hCCS-SOD1) complexes building on my recent success of structure elucidation of elusive hCCS-SOD1 complexes carried out at Liverpool. The project represents a natural continuation and an opportunity to make a major contribution to the field. State-of-the-art facilities at University of Liverpool, Synchrotrons Diamond and Soleil together with metalloproteins expertise will be a differential in achieving these ambitious goals.

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)

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, FEB 2019. (15/00062-1, 16/24686-7)