Abstract

All organisms have molecular systems that function to maintain metal ion homeostasis. The P1B-type ATPases are membrane-bound ion transporters responsible for the efflux of heavy metals and are essential for controlling the cellular levels of beneficial metals like copper and zinc and removing toxic ones like cadmium and lead. Malfunctioning copper ATPases in humans result in inherited neurological disorders like Menkes' syndrome and Wilson's disease. The Wilson ATPase has also been implicated in promoting resistance to the anticancer drugs cisplatin and carboplatin. The mechanisms of metal transport across membranes by these ATPases are not well understood. The goal of this proposal is to crystallize and determine the structure of CopA from A. fulgidus, a well characterized copper transporting P1B-type ATPase with strong identity to both the Menkes' and Wilson's proteins. Structural characterization of CopA will help to elucidate the mechanism of copper transport across cell membranes and will provide new insight into its human homologues that may be relevant to the treatment of disease and the improvement of platinum based antitumor drugs. The structure of a P1 B-type ATPase will be the first of its kind.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM073457-02
Application #
7025756
Study Section
Special Emphasis Panel (ZRG1-F04B (20))
Program Officer
Fabian, Miles
Project Start
2005-03-01
Project End
2008-02-29
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$45,976
Indirect Cost

  Institution

Name
Northwestern University at Chicago
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201

  Publications

Agarwal, Sorabh; Hong, Deli; Desai, Nirav K et al. (2010) Structure and interactions of the C-terminal metal binding domain of Archaeoglobus fulgidus CopA. Proteins 78:2450-8
Sazinsky, Matthew H; LeMoine, Benjamin; Orofino, Maria et al. (2007) Characterization and structure of a Zn2+ and [2Fe-2S]-containing copper chaperone from Archaeoglobus fulgidus. J Biol Chem 282:25950-9
Rosenzweig, Amy C; Sazinsky, Matthew H (2006) Structural insights into dioxygen-activating copper enzymes. Curr Opin Struct Biol 16:729-35
Sazinsky, Matthew H; Agarwal, Sorabh; Arguello, Jose M et al. (2006) Structure of the actuator domain from the Archaeoglobus fulgidus Cu(+)-ATPase. Biochemistry 45:9949-55
Sazinsky, Matthew H; Mandal, Atin K; Arguello, Jose M et al. (2006) Structure of the ATP binding domain from the Archaeoglobus fulgidus Cu+-ATPase. J Biol Chem 281:11161-6