Date

March 2006

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Environmental and Biomolecular Systems

Institution

Oregon Health & Science University

Abstract

The human copper chaperone to superoxide dismutase (hCCS) is a zinc and copper containing protein that delivers copper to the active site of the cytoplasmic protein superoxide dismutase (SOD). hCCS is a three domain protein with three possible copper binding sites: Domain I is called the Atx-like domain and contains the copper binding motif MXCXXC; Domain II is the SOD-like domain and includes the slightly altered histidine rich copper binding site seen in SOD; and Domain III is a short C-terminal tail that has the copper binding motif of CXC. Studies of the WT protein using EXAFS showed that the protein contained a binuclear copper-sulfur cluster. Initially, it was unknown whether this cluster was formed between domain I and domain II of the protein or formed intermolecularly between two hCCS monomers. Further studies, on the cysteine to serine mutants of the residues in the Domain I and Domain II motifs, showed that while the Domain I motif is capable of binding Cu(I), it is Domain III that is the site of the copper cluster and the cluster is formed between two hCCS monomers. Additional studies with cysteine to alanine mutants of the residues in the copper binding motifs of Domain I and Domain III showed that Domain III is not only the site of the copper cluster but also the site of transfer of copper from hCCS to SOD and also a imerization interface for hCCS. While Domain I can bind copper and may play a role in regulation of activity, it is Domain III that contains the activity of hCCS.

Identifier

doi:10.6083/M4BG2KW6

School

OGI School of Science and Engineering

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