A conserved domain of about 70 amino acid residues has been found [1] in a number of proteins that transport or detoxify heavy metals. This domain contains two conserved cysteines that could be involved in the binding of these metals. The domain has been termed Heavy-Metal-Associated (HMA).

Solution structure of the fourth HMA domain of the Menkes copper-transporting ATPase shows a well defined structure comprising a four-stranded antiparallel β-sheet and two α helices packed in an α-β sandwich fold (see <PDB:1AW0>) [2]. This fold is common to other domains and is classified as "ferredoxin-like".

Some of the proteins containing an HMA domain are listed below.

• A variety of cation transport ATPases (E1-E2 ATPases) (see <PDOC00139>). The human copper ATPAses ATP7A and ATP7B which are respectively involved in Menke's and Wilson's diseases. ATP7A and ATP7B both contain 6 tandem copies of the HMA domain. The copper ATPases CCC2 from budding yeast, copA from Enterococcus faecalis and synA from Synechococcus contain one copy of the HMA domain. The cadmium ATPases cadA from Bacillus firmus and from plasmid pI258 from Staphylococcus aureus also contain a single HMA domain, while a chromosomal Staphylococcus aureus cadA contains two copies. Other, less characterized ATPases that contain the HMA domain are: fixI from Rhizobium meliloti, pacS from Synechococcus strain PCC 7942), Mycobacterium leprae ctpA and ctpB and Escherichia coli hypothetical protein yhhO. In all these ATPases the HMA domain(s) are located in the N-terminal section.
• Mercuric reductase (EC 1.16.1.1) (gene merA) which is generally encoded by plasmids carried by mercury-resistant Gram-negative bacteria. Mercuric reductase is a class-1 pyridine nucleotide-disulphide oxidoreductase (see <PDOC00073>). There is generally one HMA domain (with the exception of a chromosomal merA from Bacillus strain RC607 which has two) in the N- terminal part of merA.
• Mercuric transport protein periplasmic component (gene merP), also encoded by plasmids carried by mercury-resistant Gram-negative bacteria. It seems to be a mercury scavenger that specifically binds to one Hg(2+) ion and which passes it to the mercuric reductase via the merT protein. The N- terminal half of merP is a HMA domain.
• Helicobacter pylori copper-binding protein copP.
• Yeast protein ATX1 [3], which could act in the transport and/or partitioning of copper.

The profile we developed spans the complete domain. The pattern is centered on the two metal-binding residues.