EC - Rhomboid protease

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IntEnz Enzyme Nomenclature


Accepted name:
rhomboid protease
Systematic name:



These endopeptidases are multi-spanning membrane proteins. Their catalytic site is embedded within the membrane and they cleave type-1 transmembrane domains. A catalytic dyad is involved in proteolysis rather than a catalytic triad, as was thought previously [14]. They are important for embryo development in Drosophila melanogaster. Rhomboid is a key regulator of EGF receptor signalling and is responsible for cleaving Spitz, the main ligand of the Drosophila EGF receptor pathway. Belongs in peptidase family S54. Parasite-encoded rhomboid enzymes are also important for invasion of host cells by Toxoplasma and the malaria parasite. Rhomboids are widely conserved from bacteria to archaea to humans [9,13].

Links to other databases

Enzymes and pathways: NC-IUBMB , BRENDA , ExplorEnz , ENZYME@ExPASy , KEGG , MetaCyc , MEROPS , UniPathway
Structural data: CSA , EC2PDB
UniProtKB/Swiss-Prot: (89) [show] [UniProt]


  1. Urban, S. and Wolfe, M.S.
    Reconstitution of intramembrane proteolysis in vitro reveals that pure rhomboid is sufficient for catalysis and specificity.
    Proc. Natl. Acad. Sci. USA 102: 1883-1888 (2005). [PMID: 15684070]
  2. Brossier F., Jewett T., Sibley D.L. and Urban, S.
    A spatially-localized rhomboid protease cleaves cell surface adhesins essential for invasion by Toxoplasma.
    Proc. Natl. Acad. Sci. USA 102: 4146-4151 (2005). [PMID: 15753289]
  3. Herlan, M., Bornhövd, C., Hell, K., Neupert, W. and Reichert, A.S.
    Alternative topogenesis of Mgm1 and mitochondrial morphology depend on ATP and a functional import motor.
    J. Cell. Biol. 165: 167-173 (2004). [PMID: 15096522]
  4. Pascall, J.C. and Brown, K.D.
    Intramembrane cleavage of ephrinB3 by the human rhomboid family protease, RHBDL2.
    Biochem. Biophys. Res. Commun. 317: 244-252 (2004). [PMID: 15047175]
  5. Sík, A., Passer, B.J., Koonin, E.V. and Pellegrini, L.
    Self-regulated cleavage of the mitochondrial intramembrane-cleaving protease PARL yields Pβ, a nuclear-targeted peptide.
    J. Biol. Chem. 279: 15323-15329 (2004). [PMID: 14732705]
  6. Urban, S. and Freeman, M.
    Substrate specificity of rhomboid intramembrane proteases is governed by helix-breaking residues in the substrate transmembrane domain.
    Mol. Cell. 11: 1425-1434 (2003). [PMID: 12820957]
  7. Herlan, M., Vogel, F., Bornhövd, C., Neupert, W. and Reichert, A.S.
    Processing of Mgm1 by the rhomboid-type protease Pcp1 is required for maintenance of mitochondrial morphology and of mitochondrial DNA.
    J. Biol. Chem. 278: 27781-27788 (2003). [PMID: 12707284]
  8. McQuibban, G.A., Saurya, S. and Freeman, M.
    Mitochondrial membrane remodelling regulated by a conserved rhomboid protease.
    Nature 423: 537-541 (2003). [PMID: 12774122]
  9. Koonin, E.V., Makarova, K.S., Rogozin, I.B., Davidovic, L., Letellier, M.-C. and Pellegrini, L.
    The rhomboids: a nearly ubiquitous family of intramembrane serine proteases that probably evolved by multiple ancient horizontal gene transfers.
    Genome Biol. 4: R19.1-12 (2003). [PMID: 12620104]
  10. Urban, S. and Freeman, M.
    Intramembrane proteolysis controls diverse signalling pathways throughout evolution.
    Curr. Opin. Genet. Dev. 12: 512-518 (2002). [PMID: 12200155]
  11. Urban, S., Schlieper, D. and Freeman, M.
    Conservation of intramembrane proteolytic activity and substrate specificity in prokaryotic and eukaryotic Rhomboids.
    Curr. Biol. 12: 1507-1512 (2002). [PMID: 12225666]
  12. Urban, S., Lee, J.R. and Freeman, M.
    A family of Rhomboid intramembrane proteases activates all Drosophila membrane-tethered EGF-like ligands.
    EMBO J. 21: 4277-4286 (2002). [PMID: 12169630]
  13. Urban, S., Lee, J.R. and Freeman, M.
    Drosophila Rhomboid-1 defines a family of putative intramembrane serine proteases.
    Cell 107: 173-182 (2001). [PMID: 11672525]
  14. Lemberg, M.K., Menendez, J., Misik, A., Garcia, M., Koth, C.M. and Freeman, M.
    Mechanism of intramembrane proteolysis investigated with purified rhomboid proteases.
    EMBO J. 24: 464-472 (2005). [PMID: 15616571]
  15. Wang, Y., Zhang, Y. and Ha, Y.
    Crystal structure of a rhomboid family intramembrane protease.
    Nature 444: 179-180 (2006). [PMID: 17051161]

[EC created 2005]