PROSITE documentation PDOC00804
Heavy-metal-associated domain signature and profile


To avoid nonspecific and/or undesirable binding and reactivity of metal ions with cellular components, organisms have evolved metal-specific systems for trafficking proteins. Although systems differ, those handling soft metal ions such as Hg(2+), Cu(+), Zn(2+), etc., all utilize heavy metal-associated (HMA) proteins and domains of ~70 amino acids with a conserved GMXCXXC motif in a βαββαβ structural fold. While the conserved cysteines define a common metal binding site in these proteins, other structural features must be utilized to create metal ion, protein partner, and contextual specificities [1,2].

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>) [3]. 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 (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 [4], 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.

Last update:

March 2022 / Text revised.


Technical section

PROSITE methods (with tools and information) covered by this documentation:

HMA_2, PS50846; Heavy-metal-associated domain profile  (MATRIX)

HMA_1, PS01047; Heavy-metal-associated domain  (PATTERN)


1AuthorsBull P.C. Cox D.W.
TitleWilson disease and Menkes disease: new handles on heavy-metal transport.
SourceTrends Genet. 10:246-252(1994).
PubMed ID8091505

2AuthorsLedwidge R. Hong B. Doetsch V. Miller S.M.
TitleNmerA of Tn501 mercuric ion reductase: structural modulation of the pKa values of the metal binding cysteine thiols.
SourceBiochemistry 49:8988-8998(2010).
PubMed ID20828160

3AuthorsGitschier J. Moffat B. Reilly D. Wood W.I. Fairbrother W.J.
TitleSolution structure of the fourth metal-binding domain from the Menkes copper-transporting ATPase.
SourceNat. Struct. Biol. 5:47-54(1998).
PubMed ID9437429

4AuthorsLin S.-J. Culotta V.C.
TitleThe ATX1 gene of Saccharomyces cerevisiae encodes a small metal homeostasis factor that protects cells against reactive oxygen toxicity.
SourceProc. Natl. Acad. Sci. U.S.A. 92:3784-3788(1995).
PubMed ID7731983

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