InterPro domain: IPR035952

This domain is found in serine peptidases belonging to the MEROPS peptidase family S54 (Rhomboid, clan ST). They are integral membrane proteins related to the Drosophila melanogaster (Fruit fly) rhomboid protein P20350 . Members of this family are found in archaea, bacteria and eukaryotes.

The rhomboid protease cleaves type-1 transmembrane domains using a catalytic dyad composed of serine and histidine. The active site is embedded within the membrane and the active site residues are on different transmembrane regions. From the tertiary structure of the Escherichia coli homologue GlpG [ 1 ] it was shown that hydrolysis occurs in a fluid filled cavity within the membrane. Initially, a catalytic triad including a highly conserved asparagine had been proposed, but this residue has been shown not to be essential [ 2 ]. Drosophila rhomboid cleaves the transmembrane proteins Spitz, Gurken and Keren within their transmembrane domains to release a soluble TGFalpha-like growth factor. Cleavage occurs in the Golgi, following translocation of the substrates from the endoplasmic reticulum membrane by Star, another transmembrane protein. The growth factors are then able to activate the epidermal growth factor receptor [ 3 , 4 ].

Few substrates of mammalian rhomboid homologues have been determined, but rhomboid-like protein 2 has been shown to cleave ephrin B3 [ 5 ]. Parasite-encoded rhomboid enzymes are also important for invasion of host cells by Toxoplasma and the malaria parasite. Invasion of host cells first requires their recognition and this is achieved by parasite transmembrane adhesins interacting with host cell receptors. Before the parasite can enter a host cell the adhesins must be released by cleavage. In Toxoplasma rhomboid TgROM5 cleaves the adhesins, and in Plasmodium, which lacks a TgROM5 orthologue, PfROMs 1 and 4 cleave the diverse array of malaria parasite adhesins [ 6 ].

This entry represents a six transmembrane helix rhomboid domain. This entry also includes derlins, inactive members of the rhomboid family of intramembrane proteases which lack an active site Ser-His dyad but retain the overall rhomboid architecture [ 7 ].

1. Crystal structure of a rhomboid family intramembrane protease. Nature 444, 179-80
2. Mechanism of intramembrane proteolysis investigated with purified rhomboid proteases. EMBO J. 24, 464-72
3. rhomboid, a gene required for dorsoventral axis establishment and peripheral nervous system development in Drosophila melanogaster. Genes Dev. 4, 190-203
4. Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases. Cell 107, 173-82
5. Intramembrane cleavage of ephrinB3 by the human rhomboid family protease, RHBDL2. Biochem. Biophys. Res. Commun. 317, 244-52
6. Two Plasmodium rhomboid proteases preferentially cleave different adhesins implicated in all invasive stages of malaria. PLoS Pathog. 2, e113
7. Derlin-1 is a rhomboid pseudoprotease required for the dislocation of mutant α-1 antitrypsin from the endoplasmic reticulum. Nat Struct Mol Biol 18, 1147-52