Rhomboid protease

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Rhomboid
Rhomboid protease GlpG 3ZMH.png
Escherichia coli rhomboid protease GlpG in complex with a beta-lactam inhibitor (yellow) bound to the catalytic serine residue. From PDB: 3ZMH ​. [1]
Identifiers
SymbolRhomboid
Pfam PF01694
Pfam clan CL0207
InterPro IPR002610
MEROPS S54
SCOP2 144092 / SCOPe / SUPFAM
OPM superfamily 165
OPM protein 2ic8
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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. [2] 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.

Contents

Intramembrane proteases

Rhomboids are intramembrane serine proteases. [3] [4] [5] [6] : Abstract  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

Rhomboids were first named after a mutation in the fruit fly Drosophila , discovered in a famous genetic screen that led to a Nobel Prize for Christiane Nüsslein-Volhard and Eric Wieschaus. [7] In that screen they found a number of mutants with similar phenotypes: ‘pointy’ embryonic head skeletons. [6] : 192  They named them each with a pointy-themed name – one was rhomboid. At first this was noticed because a mutation disrupted development, [8] : 237  genetic analysis later proved that this group of genes were members of the epidermal growth factor (EGF) receptor signalling pathway, [9] [10] [6] : 192  [8] : abstract, 239  and that rhomboid was needed to generate the signal that activates the EGF receptor. [11] [12] [6] : 192  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 [6] : 192, Fig 1  and other members of the family were the first known intramembrane serine proteases. [3]

Function

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. [3] Since then, many other important biological functions have been proposed. [6] : 196  [13]

Structure

Rhomboids were the first intramembrane proteases for which a high resolution crystal structure was solved. [36] [37] [38] [39] [40] These structures confirmed predictions that rhomboids have a core of six transmembrane domains, and that the catalytic site depends on a serine and histidine catalytic dyad. The structures 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. [41] The active site of rhomboid protease is in a hydrophilic indentation, in principle accessible to water from the bulk solution. [36] [37] [38] [39] [40] However, it has been proposed that there might be an auxiliary mechanism to facilitate access of water molecules to the catalytic dyad at the bottom of the active site to ensure catalytic efficiency. [42]

The active site of rhomboid protease is protected laterally from the lipid bilayer by its six constituent transmembrane helices, suggesting that substrate access to rhomboid active site is regulated. One area of uncertainty has been the route of substrate access. Substrates were initially proposed to enter between transmembrane segments (TMSs) 1 and 3, [36] [39] but current evidence strongly supports an alternative access point, between TMSs 2 and 5. [37] [38] [40] [43] [44] This notion is also supported by the fact that mutations in TMS 5 have only a marginal effect on the thermodynamic stability of rhomboid, unlike other regions of the molecule. [45] Very recently, the first ever co-crystal structure of an intramembrane protease [46] – Escherichia coli 's version of the rhomboid protease GlpG [8] : 239  – and a substrate-derived peptide bound in the active site [46] confirms and extends this substrate access model and provides implications for the mechanism of other rhomboid-superfamily proteins.[ citation needed ]E. coli's GlpG is unusual for its low enzyme/substrate binding affinity. [8] : 239  The details of how a substrate TMS may be recognized by rhomboid are however still unclear. Some authors propose that substrate access involves a large lateral displacement movement of TMS 5 to open up the core of rhomboid. [37] [43] Other reports instead suggest that large lateral movement of TMS 5 is not required, [47] and propose that the surface of TMSs 2 and 5 rather serves as an "intramembrane exosite" mediating the recognition of substrate TMS. [46] [48] The rhomboid ortholog in D. suzukii is Dsuz\DS10_00004507. [49]

Enzymatic specificity

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 domain 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), [50] or even multipass membrane proteins could act as rhomboid substrates. [51] 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 at the site of cleavage as the main substrate determinant. [52] More recently, it has been found that rhomboid substrates are defined by two separable elements: the transmembrane domain and a primary sequence motif in or immediately adjacent to it. [48] This recognition motif directs where the substrate is cleaved, which can occur either within, or just outside, the transmembrane domain, in the juxtamembrane region. [48] In the former case helix destabilising residues downstream in substrate TMS are also necessary for efficient cleavage. [48] A detailed enzyme kinetics analysis has in fact shown that the recognition motif interactions with rhomboid active site determine the kcat of substrate cleavage. [53] The principles of substrate TMS recognition by rhomboid remain poorly understood, but numerous lines of evidence indicate that rhomboids (and perhaps also other intramembrane proteases) somehow recognise the structural flexibility or dynamics of transmembrane domain of their substrates. [42] [54] Full appreciation of the biophysical and structural principles involved will require structural characterisation of the complex of rhomboid with the full transmembrane substrate. [55] As a first step towards this goal, a recent co-crystal structure of the enzyme in complex with a substrate-derived peptide containing mechanism-based inhibitor explains the observed recognition motif sequence preferences in rhomboid substrates structurally, and provides a significant advance in the current understanding of rhomboid specificity and mechanism of rhomboid-family proteins. [46]

In some Gram-negative bacteria, including Shewanella and Vibrio , up to thirteen 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. [56]

Medical significance

The diversity of biological functions already known to depend on rhomboids is reflected in evidence that rhomboids play a role in a variety of diseases including cancer,[ citation needed ] parasite infection, [13] and diabetes.[ citation needed ] It is important to note, however, that there is no case yet established where a precise medical significance is fully validated. [6]

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. [57]

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 [58] (also known as RHBDF1 and RHBDF2). iRhoms can promote the ER associated degradation (ERAD) of EGF receptor ligands in Drosophila, thus providing a mechanism for regulating EGF receptor activity in the brain. [59] This implies that the fundamental cellular quality control mechanism is exploited by multicellular organisms to regulate signalling between cells. In mice, iRhoms are key trafficking chaperones required for the ER export of ADAM17/TACE and its maturation. iRhoms are thus required for the TNF-alpha and EGF receptor signalling, making them medically highly attractive. [59] [60] [61] [62] [63]

Phylogenetic analysis indicates that rhomboids are in fact members of a larger rhomboid-like superfamily or clan, which includes the derlin proteins, also involved in ERAD. [64]

Kinetoplastids have an unusually small rhomboid family repertoire, in Trypanosoma brucei XP 001561764 and XP 001561544, and in T. cruzi XP 805971, XP 802860, and XP 821055. [65]

Various rhomboid family proteins are vital to Toxoplasma gondii virulence and motility, including TgMIC2, TgMIC6, various AMA1 variants including TgAMA1, TgROM1, TgROM4, and TgROM5. [66]

Trypanosome mitochondria have TimRhom I and TimRhom II (two rhomboid family members with proteolytic function deactivated) in their presequence translocases. The difficulty in finding greater similarity either to eukaryotic or bacterial relatives may mean these came as part of the original mitochondrial progenitor. [67] Rhomboid-relatives may be membrane transport proteins in the ERAD and SELMA systems. [67] : 105 

iRhoms

iRhoms are rhomboid-like proteins, but are not proteases. As with rhomboids they were first discovered in Drosophilae. To the contrary of rhomboids, however, iRhoms inhibit EGFr signaling. Knockout mice for iRhom2 have severe immune compromise. [8] : 243, iRhoms 

Related Research Articles

<span class="mw-page-title-main">Proteolysis</span> Breakdown of proteins into smaller polypeptides or amino acids

Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, but may also occur by intra-molecular digestion.

<span class="mw-page-title-main">Protease</span> Enzyme that cleaves other proteins into smaller peptides

A protease is an enzyme that catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products. They do this by cleaving the peptide bonds within proteins by hydrolysis, a reaction where water breaks bonds. Proteases are involved in numerous biological pathways, including digestion of ingested proteins, protein catabolism, and cell signaling.

A signal peptide is a short peptide present at the N-terminus of most newly synthesized proteins that are destined toward the secretory pathway. These proteins include those that reside either inside certain organelles, secreted from the cell, or inserted into most cellular membranes. Although most type I membrane-bound proteins have signal peptides, the majority of type II and multi-spanning membrane-bound proteins are targeted to the secretory pathway by their first transmembrane domain, which biochemically resembles a signal sequence except that it is not cleaved. They are a kind of target peptide.

<span class="mw-page-title-main">Serine protease</span> Class of enzymes

Serine proteases are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. Serine proteases fall into two broad categories based on their structure: chymotrypsin-like (trypsin-like) or subtilisin-like.

Protease-activated receptors(PAR) are a subfamily of related G protein-coupled receptors that are activated by cleavage of part of their extracellular domain. They are highly expressed in platelets, and also on endothelial cells, fibroblasts, immune cells, myocytes, neurons, and tissues that line the gastrointestinal tract.

In molecular biology, the Signal Peptide Peptidase (SPP) is a type of protein that specifically cleaves parts of other proteins. It is an intramembrane aspartyl protease with the conserved active site motifs 'YD' and 'GxGD' in adjacent transmembrane domains (TMDs). Its sequences is highly conserved in different vertebrate species. SPP cleaves remnant signal peptides left behind in membrane by the action of signal peptidase and also plays key roles in immune surveillance and the maturation of certain viral proteins.

<span class="mw-page-title-main">Gamma secretase</span>

Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most well-known substrate of gamma secretase is amyloid precursor protein, a large integral membrane protein that, when cleaved by both gamma and beta secretase, produces a short 37-43 amino acid peptide called amyloid beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as Notch, ErbB4, E-cadherin, N-cadherin, ephrin-B2, or CD44.

<span class="mw-page-title-main">Presenilin</span>

Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's disease by Peter St George-Hyslop. Vertebrates have two presenilin genes, called PSEN1 that codes for presenilin 1 (PS-1) and PSEN2 that codes for presenilin 2 (PS-2). Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm C. elegans has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1.

<span class="mw-page-title-main">Alpha secretase</span> Family of proteolytic enzymes

Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein (APP) in its transmembrane region. Specifically, alpha secretases cleave within the fragment that gives rise to the Alzheimer's disease-associated peptide amyloid beta when APP is instead processed by beta secretase and gamma secretase. The alpha-secretase pathway is the predominant APP processing pathway. Thus, alpha-secretase cleavage precludes amyloid beta formation and is considered to be part of the non-amyloidogenic pathway in APP processing. Alpha secretases are members of the ADAM family, which are expressed on the surfaces of cells and anchored in the cell membrane. Several such proteins, notably ADAM10, have been identified as possessing alpha-secretase activity. Upon cleavage by alpha secretases, APP releases its extracellular domain - a fragment known as APPsα - into the extracellular environment in a process known as ectodomain shedding.

<span class="mw-page-title-main">Caspase 3</span> Protein-coding gene in the species Homo sapiens

Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the CASP3 gene. CASP3 orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

<span class="mw-page-title-main">Presenilin-1</span> Protein-coding gene in the species Homo sapiens

Presenilin-1(PS-1) is a presenilin protein that in humans is encoded by the PSEN1 gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta (Aβ) from amyloid-beta precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease.

Membrane-bound transcription factor site-2 protease, also known as S2P endopeptidase or site-2 protease (S2P), is an enzyme encoded by the MBTPS2 gene which liberates the N-terminal fragment of sterol regulatory element-binding protein (SREBP) transcription factors from membranes. S2P cleaves the transmembrane domain of SREPB, making it a member of the class of intramembrane proteases.

<span class="mw-page-title-main">Mitochondrial antiviral-signaling protein</span> Protein-coding gene in the species Homo sapiens

Mitochondrial antiviral-signaling protein (MAVS) is a protein that is essential for antiviral innate immunity. MAVS is located in the outer membrane of the mitochondria, peroxisomes, and mitochondrial-associated endoplasmic reticulum membrane (MAM). Upon viral infection, a group of cytosolic proteins will detect the presence of the virus and bind to MAVS, thereby activating MAVS. The activation of MAVS leads the virally infected cell to secrete cytokines. This induces an immune response which kills the host's virally infected cells, resulting in clearance of the virus.

<span class="mw-page-title-main">PARL</span> Protein-coding gene in the species Homo sapiens

Presenilins-associated rhomboid-like protein, mitochondrial (PSARL), also known as PINK1/PGAM5-associated rhomboid-like protease (PARL), is an inner mitochondrial membrane protein that in humans is encoded by the PARL gene on chromosome 3. It is a member of the rhomboid family of intramembrane serine proteases. This protein is involved in signal transduction and apoptosis, as well as neurodegenerative diseases and type 2 diabetes.

<span class="mw-page-title-main">RHBDF1</span> Protein-coding gene in the species Homo sapiens

Inactive rhomboid protein 1 (iRhom1) also known as rhomboid 5 homolog 1 or rhomboid family member 1 (RHBDF1) is a protein that in humans is encoded by the RHBDF1 gene. The alternative name iRhom1 has been proposed, in order to clarify that it is a catalytically inactive member of the rhomboid family of intramembrane serine proteases.

<span class="mw-page-title-main">RHBDF2</span> Protein-coding gene in the species Homo sapiens

Rhomboid family member 2 is a protein that in humans is encoded by the RHBDF2 gene. The alternative name iRhom2 has been proposed, in order to clarify that it is a catalytically inactive member of the rhomboid family of intramembrane serine proteases.

<span class="mw-page-title-main">Notch proteins</span>

Notch proteins are a family of type 1 transmembrane proteins that form a core component of the Notch signaling pathway, which is highly conserved in metazoans. The Notch extracellular domain mediates interactions with DSL family ligands, allowing it to participate in juxtacrine signaling. The Notch intracellular domain acts as a transcriptional activator when in complex with CSL family transcription factors. Members of this type 1 transmembrane protein family share several core structures, including an extracellular domain consisting of multiple epidermal growth factor (EGF)-like repeats and an intracellular domain transcriptional activation domain (TAD). Notch family members operate in a variety of different tissues and play a role in a variety of developmental processes by controlling cell fate decisions. Much of what is known about Notch function comes from studies done in Caenorhabditis elegans (C.elegans) and Drosophila melanogaster. Human homologs have also been identified, but details of Notch function and interactions with its ligands are not well known in this context.

Intramembrane proteases (IMPs), also known as intramembrane-cleaving proteases (I-CLiPs), are enzymes that have the property of cleaving transmembrane domains of integral membrane proteins. All known intramembrane proteases are themselves integral membrane proteins with multiple transmembrane domains, and they have their active sites buried within the lipid bilayer of cellular membranes. Intramembrane proteases are responsible for proteolytic cleavage in the cell signaling process known as regulated intramembrane proteolysis (RIP).

<span class="mw-page-title-main">Rhomboid-related protein 2</span> Protein-coding gene in the species Homo sapiens

Rhomboid-related protein 2 is a protein that in humans is encoded by the RHBDL2 gene.

<span class="mw-page-title-main">Spitz (protein)</span> Protein in Drosophila melanogaster

Spitz is a protein in Drosophila species which is the major activator of their epidermal growth factor receptor (EGFR).

References

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