Intramembrane proteases (IMPs), also known as intramembrane-cleaving proteases (I-CLiPs), are enzymes that have the property of cleaving

transmembrane domain A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid b ...

s of

integral membrane proteins An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a signif ...

. All known intramembrane proteases are themselves integral membrane proteins with multiple transmembrane domains, and they have their active sites buried within the

lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many ...

of cellular

membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. ...

s. Intramembrane proteases are responsible for proteolytic cleavage in the

cell signaling In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...

process known as regulated intramembrane proteolysis (RIP). Intramembrane proteases are not evolutionarily related to classical soluble

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the form ...

s, having evolved their catalytic sites by

convergent evolution Convergent evolution is the independent evolution of similar features in species of different periods or epochs in time. Convergent evolution creates analogous structures that have similar form or function but were not present in the last com ...

. Although only recently discovered, intramembrane proteases are of significant research interest because of their major biological functions and their relevance to human disease.

Classification

There are four groups of intramembrane proteases, distinguished by their

catalytic mechanism Enzyme catalysis is the increase in the rate of a process by a biological molecule, an "enzyme". Most enzymes are proteins, and most such processes are chemical reactions. Within the enzyme, generally catalysis occurs at a localized site, called ...

: *

Metalloprotease A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myog ...

Site-2 protease Membrane-bound transcription factor site-2 protease, also known as S2P endopeptidase or site-2 protease (S2P), is an enzyme () encoded by the gene which liberates the N-terminal fragment of sterol regulatory element-binding protein (SREBP) tr ...

(S2P) and S2P-like proteases * Aspartyl proteases: this group includes

presenilin 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 onse ...

, the active subunit of gamma secretase and

signal peptide peptidase 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 transmem ...

s (SPPs) and SPP-like proteases, which are distantly related to presenilin but have opposite membrane orientation *

Serine protease Serine proteases (or serine endopeptidases) 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. S ...

s: rhomboid proteases *

Glutamyl protease Glutamic proteases are a group of proteolytic enzymes containing a glutamic acid residue within the active site. This type of protease was first described in 2004 and became the sixth catalytic type of protease. Members of this group of protease ha ...

s: only one example is known,

Rce1 CAAX prenyl protease 2 is an enzyme that in humans is encoded by the ''RCE1'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''bi ...

Structure

Intramembrane proteases are

integral membrane protein An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a sign ...

s that are polytopic

transmembrane protein A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

s with multiple transmembrane helices. Their active sites are located within the transmembrane helices and form an

aqueous An aqueous solution is a solution in which the solvent is water. It is mostly shown in chemical equations by appending (aq) to the relevant chemical formula. For example, a solution of table salt, or sodium chloride (NaCl), in water would ...

environment within the

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, ...

. Most intramembrane proteases are thought to function as monomers, with the notable exception of

which is active only in the

gamma-secretase 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. T ...

protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain. Protein ...

. Examples of all four groups of intramembrane proteases have been structurally characterized by

X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angle ...

cryo-electron microscopy Cryogenic electron microscopy (cryo-EM) is a cryomicroscopy technique applied on samples cooled to cryogenic temperatures. For biological specimens, the structure is preserved by embedding in an environment of vitreous ice. An aqueous sample sol ...

Enzymatic activity

Three of the four groups of intramembrane proteases cleave their substrates within

s and the

scissile bond In molecular biology, a scissile bond is a covalent chemical bond that can be broken by an enzyme. Examples would be the cleaved bond in the self-cleaving hammerhead ribozyme or the peptide bond In organic chemistry, a peptide bond is an amide ...

is located inside the membrane. The remaining group,

glutamyl proteases, cleaves the

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein i ...

of CAAX proteins. The

kinetics Kinetics ( grc, κίνησις, , kinesis, ''movement'' or ''to move'') may refer to: Science and medicine * Kinetics (physics), the study of motion and its causes ** Rigid body kinetics, the study of the motion of rigid bodies * Chemical k ...

of intramembrane proteases are generally slower than soluble proteases.

Substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (locomotion), the surface over which an organism lo ...

specificity is not well understood and varies significantly between enzymes, with the

complex in particular known for its substrate promiscuity. Both rhomboid protease and gamma-secretase have been reported to have an unusual substrate recognition mechanism by distinguishing substrates from non-substrates only after forming a

, giving rise to their slow enzyme kinetics.

Distribution

Intramembrane proteases are found in all

domains of life In biological taxonomy, a domain ( or ) ( Latin: ''regio''), also dominion, superkingdom, realm, or empire, is the highest taxonomic rank of all organisms taken together. It was introduced in the three-domain system of taxonomy devised by Ca ...

, and all four groups are widely distributed. In

eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...

s, all

membrane-bound A biological membrane, biomembrane or cell membrane is a selectively permeable membrane that separates the interior of a cell from the external environment or creates intracellular compartments by serving as a boundary between one part of the ce ...

organelle In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' t ...

s except

peroxisome A peroxisome () is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen ...

s have at least one intramembrane protease.

Discovery

Although soluble proteases are among the earliest and best characterized enzymes, intramembrane proteases were discovered relatively recently. Intramembrane proteolysis was proposed in the 1990s by researchers studying Alzheimer's disease, such as

Dennis Selkoe Dennis J. Selkoe (born 25 September 1943) is an American physician (neurologist) known for his research into the molecular basis of Alzheimer's disease. In 1985 he became Co-Director of the Center for Neurological Diseases and from 1990, Vincent ...

, as a possible mechanism for the processing of

amyloid precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator ...

. The possibility of

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

occurring within the

membrane was initially controversial. The first intramembrane protease to be experimentally identified was

site-2 protease Membrane-bound transcription factor site-2 protease, also known as S2P endopeptidase or site-2 protease (S2P), is an enzyme () encoded by the gene which liberates the N-terminal fragment of sterol regulatory element-binding protein (SREBP) tr ...

in 1997.

References

{{DEFAULTSORT:Intramembrane Protease EC 3.4 Integral membrane proteins