Intramembrane protease

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.^[1][2][3] 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.^[4]

Intramembrane proteases are not evolutionarily related to classical soluble proteases, having evolved their catalytic sites by convergent evolution.^[5][6]

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.

Classification

Four major classes of intramembrane proteases have been discovered:^[7]

• Site-2 protease (S2P) and S2P-like proteases, which are metalloproteases^[8]
• Presenilin, the active subunit of gamma secretase, which is an aspartyl protease^[9][10]
• Signal peptide peptidases (SPPs) and SPP-like proteases, which are aspartyl proteases and are distantly related to presenilin but have opposite membrane orientation^[11][12]
• Rhomboid proteases, which are serine proteases^[13]

References

1. Brown, MS; Ye, J; Rawson, RB; Goldstein, JL (18 February 2000). "Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans.". Cell 100 (4): 391–8. doi:10.1016/S0092-8674(00)80675-3. PMID 10693756.
2. Urban, S; Freeman, M (October 2002). "Intramembrane proteolysis controls diverse signalling pathways throughout evolution.". Current opinion in genetics & development 12 (5): 512–8. doi:10.1016/s0959-437x(02)00334-9. PMID 12200155.
3. Wolfe, MS; Kopan, R (20 August 2004). "Intramembrane proteolysis: theme and variations.". Science 305 (5687): 1119–23. doi:10.1126/science.1096187. PMID 15326347.
4. Erez, E; Fass, D; Bibi, E (21 May 2009). "How intramembrane proteases bury hydrolytic reactions in the membrane.". Nature 459 (7245): 371–8. doi:10.1038/nature08146. PMID 19458713.
5. Koonin, EV; Makarova, KS; Rogozin, IB; Davidovic, L; Letellier, MC; Pellegrini, L (2003). "The rhomboids: a nearly ubiquitous family of intramembrane serine proteases that probably evolved by multiple ancient horizontal gene transfers.". Genome Biology 4 (3): R19. PMID 12620104.
6. Lemberg, M. K.; Freeman, M. (1 November 2007). "Functional and evolutionary implications of enhanced genomic analysis of rhomboid intramembrane proteases". Genome Research 17 (11): 1634–1646. doi:10.1101/gr.6425307. PMC 2045146. PMID 17938163.
7. Wolfe, M. S. (3 February 2009). "Intramembrane-cleaving Proteases". Journal of Biological Chemistry 284 (21): 13969–13973. doi:10.1074/jbc.R800039200.
8. Rawson, RB; Zelenski, NG; Nijhawan, D; Ye, J; Sakai, J; Hasan, MT; Chang, TY; Brown, MS; Goldstein, JL (December 1997). "Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs.". Molecular Cell 1 (1): 47–57. doi:10.1016/s1097-2765(00)80006-4. PMID 9659902.
9. Wolfe, MS; Xia, W; Ostaszewski, BL; Diehl, TS; Kimberly, WT; Selkoe, DJ (8 April 1999). "Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.". Nature 398 (6727): 513–7. doi:10.1038/19077. PMID 10206644.
10. De Strooper, B; Annaert, W; Cupers, P; Saftig, P; Craessaerts, K; Mumm, JS; Schroeter, EH; Schrijvers, V; Wolfe, MS; Ray, WJ; Goate, A; Kopan, R (8 April 1999). "A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.". Nature 398 (6727): 518–22. doi:10.1038/19083. PMID 10206645.
11. Weihofen, A; Binns, K; Lemberg, MK; Ashman, K; Martoglio, B (21 June 2002). "Identification of signal peptide peptidase, a presenilin-type aspartic protease.". Science 296 (5576): 2215–8. doi:10.1126/science.1070925. PMID 12077416.
12. Friedmann, E; Hauben, E; Maylandt, K; Schleeger, S; Vreugde, S; Lichtenthaler, SF; Kuhn, PH; Stauffer, D; Rovelli, G; Martoglio, B (August 2006). "SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production.". Nature Cell Biology 8 (8): 843–8. doi:10.1038/ncb1440. PMID 16829952.
13. Urban, S; Lee, JR; Freeman, M (19 October 2001). "Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases.". Cell 107 (2): 173–82. doi:10.1016/s0092-8674(01)00525-6. PMID 11672525.