{PDOC51846}
{PS51846; CNNM}
{BEGIN}
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* CNNM transmembrane domain profile *
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Proteins in  the  ancient  conserved domain protein/cyclin M (CNNM) family are
integral membrane  proteins  that  are conserved from bacteria to humans. CNNM
family members influence metal ion homeostasis through mechanisms that may not
involve direct membrane transport of the ions. Structurally, CNNMs are complex
proteins that   contain   an   extracellular  N-terminal  domain  preceding  a
transmembrane domain, a "Bateman module", which consists of two cystathionine-
beta-synthase (CBS)  domains  (see <PDOC51371>), and a C-terminal cNMP (cyclic
nucleotide monophosphate) binding domain (see <PDOC00691>) [1,2,3,4].

The CNNM  transmembrane  domain  contains four hydrophobic regions. The second
one is  the  shortest  and  the  least hydrophobic, indicating that the second
hydrophobic region  might  not  be  completely  membrane-spanning, but instead
forms a  re-entrant  loop.  Hence,  the CNNM integral membrane domain has been
proposed to  contain  three  full  membrane-spanning regions and an additional
re-entrant loop [2].

Some proteins known to contain a CNNM transmembrane domain are listed below:

 - Mammalian metal transporter CNNM1.
 - Mammalian  metal  transporter  CNNM2,  mediates transport of divalent metal
   cations.
 - Mammalian metal transporter CNNM3.
 - Mammalian metal transporter CNNM4.
 - Caenorhabditis  elegans  metal  transport  proteins cnnm-1, cnnm-2, cnnm-3,
   cnnm-4 and cnnm-5 that regulate Mg2+ homeostasis.
 - Yeast MAM3 (Mitochondria Aberrant Morphology), an integral membrane protein
   of the  vacuole, whose expression levels directly correlate with the degree
   of manganese toxicity.

The profile we developed covers the entire CNNM transmembrane domain.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.
-Last update: November 2017 / First entry.

[ 1] Yang M., Jensen L.T., Gardner A.J., Culotta V.C.
     "Manganese toxicity and Saccharomyces cerevisiae Mam3p, a member of
     the ACDP (ancient conserved domain protein) family."
     Biochem. J. 386:479-487(2005).
     PubMed=15498024; DOI=10.1042/BJ20041582
[ 2] de Baaij J.H.F., Stuiver M., Meij I.C., Lainez S., Kopplin K.,
     Venselaar H., Mueller D., Bindels R.J.M., Hoenderop J.G.J.
     "Membrane topology and intracellular processing of cyclin M2
     (CNNM2)."
     J. Biol. Chem. 287:13644-13655(2012).
     PubMed=22399287; DOI=10.1074/jbc.M112.342204
[ 3] Gulerez I., Funato Y., Wu H., Yang M., Kozlov G., Miki H., Gehring K.
     "Phosphocysteine in the PRL-CNNM pathway mediates magnesium
     homeostasis."
     EMBO Rep. 17:1890-1900(2016).
     PubMed=27856537; DOI=10.15252/embr.201643393
[ 4] Gimenez-Mascarell P., Oyenarte I., Hardy S., Breiderhoff T.,
     Stuiver M., Kostantin E., Diercks T., Pey A.L., Ereno-Orbea J.,
     Martinez-Chantar M.L., Khalaf-Nazzal R., Claverie-Martin F.,
     Mueller D., Tremblay M.L., Martinez-Cruz L.A.
     "Structural Basis of the Oncogenic Interaction of Phosphatase PRL-1
     with the Magnesium Transporter CNNM2."
     J. Biol. Chem. 292:786-801(2017).
     PubMed=27899452; DOI=10.1074/jbc.M116.759944

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