{PDOC00804}
{PS01047; HMA_1}
{PS50846; HMA_2}
{BEGIN}
*******************************************************
* 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
BetaAlphaBetaBetaAlphaBeta 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
beta-sheet  and  two  alpha helices  packed  in  an  alpha-beta  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 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  [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.

-Consensus pattern: [LIVNS]-x-{L}-[LIVMFA]-x-C-x-[STAGCDNH]-C-x(3)-[LIVFG]-
                    {LV}-x(2)-[LIV]-x(9,11)-[IVA]-x-[LVFYS]
                    [The 2 C's may bind metals]
-Sequences known to belong to this class detected by the pattern: ALL.
-Other sequence(s) detected in Swiss-Prot: 7.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Last update: March 2022 / Text revised.

[ 1] Bull P.C., Cox D.W.
     "Wilson disease and Menkes disease: new handles on heavy-metal
     transport."
     Trends Genet. 10:246-252(1994).
     PubMed=8091505
[ 2] Ledwidge R., Hong B., Doetsch V., Miller S.M.
     "NmerA of Tn501 mercuric ion reductase: structural modulation of the
     pKa values of the metal binding cysteine thiols."
     Biochemistry 49:8988-8998(2010).
     PubMed=20828160; DOI=10.1021/bi100537f
[ 3] Gitschier J., Moffat B., Reilly D., Wood W.I., Fairbrother W.J.
     "Solution structure of the fourth metal-binding domain from the Menkes
     copper-transporting ATPase."
     Nat. Struct. Biol. 5:47-54(1998).
     PubMed=9437429
[ 4] Lin S.-J., Culotta V.C.
     "The ATX1 gene of Saccharomyces cerevisiae encodes a small metal
     homeostasis factor that protects cells against reactive oxygen
     toxicity."
     Proc. Natl. Acad. Sci. U.S.A. 92:3784-3788(1995).
     PubMed=7731983

--------------------------------------------------------------------------------
PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and
distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives
(CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html
--------------------------------------------------------------------------------

{END}