Intramembrane proteases 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

Lipid bilayer

The lipid bilayer is a thin membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around cells. The cell membrane of almost all living organisms and many viruses are made of a lipid bilayer, as are the membranes surrounding the cell nucleus...

 of cellular membranes. Three major classes of intramembrane proteases have been discovered. The Site-2 protease (S2P)

Membrane-bound transcription factor peptidase, site 2

Membrane-bound transcription factor peptidase, site 2 also known as Site-2 Protease is an enzyme encoded by the gene which liberates the N-terminal fragment of sterol regulatory element binding protein transcription factors from membranes . S2P cleaves the transmembrane domain of SREPB, making...

 family are intramembrane metalloproteases. Presenilin

Presenilin

Presenilins are a family of related multi-pass transmembrane proteins that function as a part of the gamma-secretase intramembrane protease complex...

, the active subunit of gamma secretase

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...

, and the signal peptide peptidase (SPP)

Signal Peptide Peptidase

The Signal Peptide Peptidase is an intramembrane aspartyl protease with the conserved active site motifs 'YD' and 'GxGD' in in adjacent transmembrane domains . Its sequences is highly conserved in different vertebrate species...

  and SPP-like group (which are distantly related to presenilin but have opposite membrane orientation) are intramembrane aspartyl proteases

Aspartate protease

Aspartic proteases are a family of protease enzymes that use an aspartate residue for catalysis of their peptide substrates. In general, they have two highly-conserved aspartates in the active site and are optimally active at acidic pH...

. The rhomboid protease

Rhomboid protease

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...

 family are serine proteases.

Intramembrane proteases are not evolutionarily related to classical soluble proteases, having evolved their catalytic sites by convergent evolution

Convergent evolution

Convergent evolution describes the acquisition of the same biological trait in unrelated lineages.The wing is a classic example of convergent evolution in action. Although their last common ancestor did not have wings, both birds and bats do, and are capable of powered flight. The wings are...

.

Although only recently discovered, intramembrane proteases are the focus of intense interest because of their major biological functions and their implication in many human diseases.