PROSITE documentation PDOC52012
CFEM domain profile


The CFEM (Common in Fungal Extracellular Membrane) protein domain is unique to fungi, but it is not found in all fungi. Many CFEM domain proteins have been found exclusively from Ascomycota and Basidiomycota, and they were found to be enriched in pathogenic fungi. The CFEM domain is found primarily in glycosylphosphatidylinositol (GPI)-anchored cell-wall proteins, and present in one or more copies, normally with one copy near the N terminus of proteins. CFEM-containing proteins are involved in differentiation, stress response and pathogenicity. CFEM-containing proteins systematically contribute to iron acquisition during saprotrophic and pathogenic growth in filamentous mycopathogens as well as inter-species competition. CFEM proteins have been shown to bind haem and to play crucial roles in extracting it from the host haemoglobin, as well as in mediating its delivery to the fungal cel [1,2,3,4].

The CFEM domain is predominantly comprised of hybrophobic residues. CFEM domains contain eight characteristically spaced cysteine residues with the consensus sequence P-x-C-[AG]-x(2)-C-x(8,12)-C-x(1,4)-D-x(2,5)-C-x-C-x(9,14)-C-x(3,4)-C-x(15,16) (where x is any residue with its range shown). The CFEM domain adopts a helical-basket fold that consists of six α-helices, the third of which is perpendicular to a central bundle of five antiparallel helices (see <PDB:4Y7S>). Overall, the shape of the helical portion resembles a basket that is 'capped' from the top by Helix 3, whereas the long N-terminal loop appears as its 'handle'. The uniqueness of the helical-basket fold appears to stem primarily from the formation of four distinctive disulfide bonds that probably contribute to its rigidity and compactness, as well as to the distinctive orientation between its helices. These S-S bridges are formed between the eight canonical cysteine residues of the CFEM domain. Topologically, helices 2 and 4 are held together via two disulfide bridges, one formed by the first and the seventh cysteine residues (C1-C7) and the second by the second and sixth (C2-C6). Helices 3 and 5 are linked via a single disulfide bond (C5-C8), and Helix 3 is linked to an important haem-interacting loop via the C3-C4 disulfide bridge. The planar haem molecule is bound between a flat hydrophobic platform located on top of the helical basket and a peripheral N-terminal 'handle' extension. Exceptionally, an aspartic residue serves as the CFEM axial ligand, and so confers coordination of Fe(3+) haem, but not of Fe(2+) [1,2].

The profile we developed covers the entire CFEM domain.

Last update:

November 2022 / First entry.


Technical section

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

CFEM, PS52012; CFEM domain profile  (MATRIX)


1AuthorsKulkarni R.D. Kelkar H.S. Dean R.A.
TitleAn eight-cysteine-containing CFEM domain unique to a group of fungal membrane proteins.
SourceTrends. Biochem. Sci. 28:118-121(2003).
PubMed ID12633989

2AuthorsNasser L. Weissman Z. Pinsky M. Amartely H. Dvir H. Kornitzer D.
TitleStructural basis of haem-iron acquisition by fungal pathogens.
SourceNat. Microbiol. 1:16156-16156(2016).
PubMed ID27617569

3AuthorsChen L. Wang H. Yang J. Yang X. Zhang M. Zhao Z. Fan Y. Wang C. Wang J.
TitleBioinformatics and Transcriptome Analysis of CFEM Proteins in Fusarium graminearum.
SourceJ. Fungi. (Basel). 7:0-0(2021).
PubMed ID34682292

4AuthorsPeng Y.-J. Hou J. Zhang H. Lei J.-H. Lin H.-Y. Ding J.-L. Feng M.G. Ying S.-H.
TitleSystematic contributions of CFEM domain-containing proteins to iron acquisition are essential for interspecies interaction of the filamentous pathogenic fungus Beauveria bassiana.
SourceEnviron. Microbiol. 24:3693-3704(2022).
PubMed ID35523457

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