Summary: Rhomboid family
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Rhomboid protease Edit Wikipedia article
The rhomboid proteases are a family of enzymes that exist in almost all species. They are proteases: they cut the polypeptide chain of other proteins. This proteolytic cleavage is irreversible in cells, and an important type of cellular regulation. Although proteases are one of the earliest and best studied class of enzyme, rhomboids belong to a much more recently discovered type: the intramembrane proteases. What is unique about intramembrane proteases is that their active sites are buried in the lipid bilayer of cell membranes, and they cleave other transmembrane proteins within their transmembrane domains. About 30% of all proteins have transmembrane domains, and their regulated processing often has major biological consequences. Accordingly, rhomboids regulate many important cellular processes, and may be involved in a wide range of human diseases.
Rhomboids are intramembrane serine proteases. The other types of intramembrane protease are aspartyl- and metallo-proteases, respectively. The presenilins and signal peptide peptidase-like family, which are intramembrane aspartyl proteases, cleave substrates that include the Notch receptor and the amyloid precursor protein, which is implicated in Alzheimer's disease. The site-2 protease family, which are intramembrane metalloproteases, regulate among other things cholesterol biosynthesis and stress responses in bacteria. The different intramembrane protease families are evolutionarily and mechanistically unrelated, but there are clear common functional themes that link them. Rhomboids are perhaps the best characterised class.
History of rhomboid discovery
Rhomboids were first named after a mutation in the fruitfly Drosophila, discovered in a famous genetic screen that led to a Nobel Prize for Christiane Nüsslein-Volhard and Eric Wieschaus. In that screen they found a number of mutants with similar phenotypes: ‘pointy’ embryonic head skeletons. They named them each with a pointy-themed name – one was rhomboid. Genetic analysis later proved that this group of genes were members of the epidermal growth factor (EGF) receptor signalling pathway, and that rhomboid was needed to generate the signal that activates the EGF receptor. The molecular function of rhomboid took a bit longer to unravel but a combination of genetics and molecular techniques led to the discovery that Drosophila rhomboid and other members of the family were the first known intramembrane serine proteases.
Biological role of rhomboids
Rhomboids were first discovered as proteases that regulate EGF receptor signalling in Drosophila. By releasing the extracellular domain of the growth factor Spitz, from its transmembrane precursor, rhomboid triggers signalling. Since then, many other important biological functions have been proposed.
- Although less well established than in Drosophila, there is some evidence that rhomboids may participate in growth factor signalling in mammals, including humans. They have also been implicated in ephrin signalling  and the cleavage of the anticoagulant protein thrombomodulin.
- All eukaryotes have a mitochondrial rhomboid. In yeast this has been shown to control mitochondrial function and morphology by regulating membrane fusion via the cleavage of a dynamin-like GTPase called Mgm1p, the orthologue of human OPA1. In Drosophila, the mitochondrial rhomboid also regulates mitochondrial membrane fusion. In mammals too, mitochondrial function is disrupted in mutants of PARL, the mitochondrial rhomboid, but the range of functions is more complex. PARL regulates the remodelling of mitochondrial cristae, is implicated in cell death  and metabolism, and there is increasing evidence of an important role in Parkinson's Disease;
- Apicomplexan parasites like Plasmodium (the agent that causes malaria) and Toxoplasma appear to use rhomboids to cleave cell surface proteins that participate in the host invasion process; they have also been implicated in the pathogenicity of other parasites;
- A rhomboid in the Gram-negative bacterium Providencia stuartii is required for the function of the twin-arginine protein translocation (TAT) machinery.
Structure and enzyme function of rhomboids
Rhomboids were the first intramembrane proteases for which a high resolution crystal structure was solved. These structures confirmed predictions that rhomboids have a core six transmembrane domain structure, and that the catalytic site depends on a serine and histidine catalytic dyad. The structure also explained how a proteolytic reaction, which requires water molecules, can occur in the hydrophobic environment of a lipid bilayer: one of the central mysteries of intramembrane proteases. The catalytic site was shown to be a hydrophilic indentation, protected from the lipid bilayer by surrounding transmembrane domains.
One area of uncertainty is the route by which substrates get access to the rhomboid active site . Although substrates were initially proposed to enter between transmembrane domains 1 and 3, evidence now strongly supports an alternative access point, between transmembrane domains 2 and 5.
Rhomboids do not cleave all transmembrane domains. In fact, they are highly specific, with a limited number of substrates. Most natural Rhomboid substrates known so far are type 1 single transmembrane proteins, with their amino termini in the luminal/extracellular compartment. However, recent studies suggested that type 2 membrane protein (i.e. with opposite topology: the amino terminus is cytoplasmic), or even multipass membrane proteins could act as rhomboid substrates. The specificity of rhomboids underlies their ability to control functions in a wide range of biological processes and, in turn, understanding what makes a particular transmembrane domain into a rhomboid substrate can shed light on rhomboid function in different contexts.
Initial work indicated that rhomboids recognise instability of the transmembrane alpha-helix as the main substrate determinant. More recently a primary sequence motif in or immediately adjacent to the transmembrane domain has been shown to be the cardinal recognition determinant of a variety of rhomboid substrates. This recognition motif directs where the substrate is cleaved. This can occur either within the transmembrane domain or just outside the membrane. Only in the former case are helix destabilising residues also necessary. Although the structure of a rhomboid/substrate complex has not yet been solved, a recent structure of the enzyme in complex with a mechanism-based inhibitor  is consistent with the current understanding of rhomboid specificity.
In some Gram-negative bacteria, including Shewanella and Vibrio, up to thirteen proteins proteins are found with GlyGly-CTERM, a C-terminal homology domain consisting of a glycine-rich motif, a highly hydrophobic transmembrane helix, and a cluster of basic residues. This domain appears to be the recognition sequence for rhombosortase, a branch of the rhomboid protease family limited to just those bacteria with the GlyGly-CTERM domain.
Medical significance of rhomboids
The diversity of biological functions already known to depend on rhomboids is reflected in evidence that rhomboids play a role in a variety if diseases including cancer, parasite infection, and diabetes. It is important to note, however, that there is no case yet established where a precise medical significance is fully validated.
No drugs that modulate rhomboid activity have yet been reported, although a recent study has identified small molecule, mechanism-based inhibitors that could provide a basis for future drug development.
The rhomboid-like family
Rhomboid proteases appear to be conserved in all eukaryotes and the vast majority of prokaryotes. Bioinformatic analysis highlights that some members of the rhomboid family lack the amino acid residues essential for proteolysis, implying that they cannot cleave substrates. These ‘pseudoproteases’ include a subfamily that have been named the iRhoms  (also known as RHBDF1 and RHBDF2). iRhoms can promote the ER associated degradation (ERAD) of EGF receptor ligands. In Drosophila this provides a mechanism for regulating EGF receptor activity in the brain. This unexpected mechanism implies that the fundamental cellular quality control mechanism is exploited by multicellular organisms to regulate signalling between cells.
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Rhomboid family Provide feedback
This family contains integral membrane proteins that are related to Drosophila rhomboid protein P20350. Members of this family are found in bacteria and eukaryotes. Rhomboid promotes the cleavage of the membrane-anchored TGF-alpha-like growth factor Spitz, allowing it to activate the Drosophila EGF receptor. Analysis has shown that Rhomboid-1 is an intramembrane serine protease  ( EC:188.8.131.52). Parasite-encoded rhomboid enzymes are also important for invasion of host cells by Toxoplasma and the malaria parasite .
Bier E, Jan LY, Jan YN; , Genes Dev 1990;4:190-203.: rhomboid, a gene required for dorsoventral axis establishment and peripheral nervous system development in Drosophila melanogaster. PUBMED:2110920 EPMC:2110920
Koonin EV, Makarova KS, Rogozin IB, Davidovic L, Letellier MC, Pellegrini L; , Genome Biol 2003;4:R19.: The rhomboids: a nearly ubiquitous family of intramembrane serine proteases that probably evolved by multiple ancient horizontal gene transfers. PUBMED:12620104 EPMC:12620104
Urban S, Wolfe MS; , Proc Natl Acad Sci U S A. 2005;102:1883-1888.: Reconstitution of intramembrane proteolysis in vitro reveals that pure rhomboid is sufficient for catalysis and specificity. PUBMED:15684070 EPMC:15684070
Brossier F, Jewett TJ, Sibley LD, Urban S; , Proc Natl Acad Sci U S A. 2005;102:4146-4151.: A spatially localized rhomboid protease cleaves cell surface adhesins essential for invasion by Toxoplasma. PUBMED:15753289 EPMC:15753289
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR022764
In the MEROPS database peptidases and peptidase homologues are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry based on a common structural fold:
- Each clan is identified with two letters, the first representing the catalytic type of the families included in the clan (with the letter 'P' being used for a clan containing families of more than one of the catalytic types serine, threonine and cysteine). Some families cannot yet be assigned to clans, and when a formal assignment is required, such a family is described as belonging to clan A-, C-, M-, N-, S-, T- or U-, according to the catalytic type. Some clans are divided into subclans because there is evidence of a very ancient divergence within the clan, for example MA(E), the gluzincins, and MA(M), the metzincins.
- Peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; N, asparagine; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In the case of the asparagine endopeptidases, the nucleophile is asparagine and all are self-processing endopeptidases.
In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding.
Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes [PUBMED:7845208]. They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Many families of serine protease have been identified, these being grouped into clans on the basis of structural similarity and other functional evidence [PUBMED:7845208]. Structures are known for members of the clans and the structures indicate that some appear to be totally unrelated, suggesting different evolutionary origins for the serine peptidases [PUBMED:7845208].
Not withstanding their different evolutionary origins, there are similarities in the reaction mechanisms of several peptidases. Chymotrypsin, subtilisin and carboxypeptidase C have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nucleophile, aspartate as an electrophile, and histidine as a base [PUBMED:7845208]. The geometric orientations of the catalytic residues are similar between families, despite different protein folds [PUBMED:7845208]. The linear arrangements of the catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (PA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) [PUBMED:7845208, PUBMED:8439290].
This group of proteins contain 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 SWISSPROT. Members of this family are found in archaea, bacteria and eukaryotes.
The D. melanogaster rhomboid protease cleaves type-1 transmembrane domains using a catalytic triad composed of serine, histidine and asparagine contributed by different transmembrane domains. It 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 [PUBMED:2110920, PUBMED:11672525].
Few substrates of mammalian rhomboid homologues have been determined, but rhomboid-like protein 2 (MEROPS S54.002) has been shown to cleave ephrin B3 [PUBMED:15047175]. Parasite-encoded rhomboid enzymes are also important for invasion of host cells by Toxoplasma and the malaria parasite.
In Saccharomyces cerevisiae (Baker's yeast) the Pcp1 (MDM37) protein (MEROPS S54.007) is a mitochondrial endopeptidase required for the activation of cytochrome c peroxidase and for the processing of the mitochondrial dynamin-like protein Mgm1 [PUBMED:12417197, PUBMED:12707284]. Mutations in Pcp1 result in cells have fragmented mitochondria, which have very few short tubulues [PUBMED:11907266].This entry represents the 6 transmembrane helix rhomboid domain.
|Cellular component||integral to membrane (GO:0016021)|
|Molecular function||serine-type endopeptidase activity (GO:0004252)|
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- the UniProt description of the protein sequence
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This clan contains proteins from both bacteria and eukaryotes. The Rhomboid protein is an intramembrane serine protease which is involved in epidermal growth factor (EGF)-dependent signalling pathways . The DER1 family is involved in degradation of misfolded ER proteins .
The clan contains the following 3 members:DER1 DUF1751 Rhomboid
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
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Curation and family details
|Seed source:||Pfam-B_1399 (release 4.1)|
|Author:||Sohrmann M, Bateman A|
|Number in seed:||65|
|Number in full:||7854|
|Average length of the domain:||148.00 aa|
|Average identity of full alignment:||23 %|
|Average coverage of the sequence by the domain:||48.95 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||17|
|Download:||download the raw HMM for this family|
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Rhomboid domain has been found. There are 16 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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