PROSITE documentation PDOC51846
CNNM transmembrane domain profile


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-β-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.

Last update:

November 2017 / First entry.


Technical section

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

CNNM, PS51846; CNNM transmembrane domain profile  (MATRIX)


1AuthorsYang M. Jensen L.T. Gardner A.J. Culotta V.C.
TitleManganese toxicity and Saccharomyces cerevisiae Mam3p, a member of the ACDP (ancient conserved domain protein) family.
SourceBiochem. J. 386:479-487(2005).
PubMed ID15498024

2Authorsde 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.
TitleMembrane topology and intracellular processing of cyclin M2 (CNNM2).
SourceJ. Biol. Chem. 287:13644-13655(2012).
PubMed ID22399287

3AuthorsGulerez I. Funato Y. Wu H. Yang M. Kozlov G. Miki H. Gehring K.
TitlePhosphocysteine in the PRL-CNNM pathway mediates magnesium homeostasis.
SourceEMBO Rep. 17:1890-1900(2016).
PubMed ID27856537

4AuthorsGimenez-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.
TitleStructural Basis of the Oncogenic Interaction of Phosphatase PRL-1 with the Magnesium Transporter CNNM2.
SourceJ. Biol. Chem. 292:786-801(2017).
PubMed ID27899452

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