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 responsible for proteolytic cleavage in the cell signaling process known as regulated intramembrane proteolysis (RIP).[1][5]

Intramembrane proteases are not evolutionarily related to classical soluble proteases, having evolved their catalytic sites by convergent evolution.[6][7][8]

Although only recently discovered, intramembrane proteases are of significant research interest because of their major biological functions and their relevance to human disease.[5]

Classification

There are four groups of intramembrane proteases, distinguished by their catalytic mechanism:[5]

Structure

Intramembrane proteases are integral membrane proteins that are polytopic transmembrane proteins with multiple transmembrane helices.[5][17] Their active sites are located within the transmembrane helices and form an aqueous environment within the hydrophobic lipid bilayer. Most intramembrane proteases are thought to function as monomers, with the notable exception of presenilin which is active only in the gamma-secretase protein complex.[17]

Examples of all four groups of intramembrane proteases have been structurally characterized by X-ray crystallography or cryo-electron microscopy.[17]

Enzymatic activity

Three of the four groups of intramembrane proteases cleave their substrates within transmembrane domains and the scissile bond is located inside the membrane. The remaining group, Rce1 glutamyl proteases, cleaves the C-terminus of CAAX proteins.[17] The kinetics of intramembrane proteases are generally slower than soluble proteases.[18][19] Substrate specificity is not well understood and varies significantly between enzymes, with the gamma-secretase complex in particular known for its substrate promiscuity.[18][20] 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 protein complex, giving rise to their slow enzyme kinetics.[19]

Distribution

Intramembrane proteases are found in all domains of life, and all four groups are widely distributed.[5] In eukaryotes, all membrane-bound organelles except peroxisomes have at least one intramembrane protease.[5]

Discovery

Although soluble proteases are among the earliest and best characterized enzymes, intramembrane proteases were discovered relatively recently.[21][18] Intramembrane proteolysis was proposed in the 1990s by researchers studying Alzheimer's disease, such as Dennis Selkoe, as a possible mechanism for the processing of amyloid precursor protein.[22] The possibility of hydrolysis occurring within the hydrophobic membrane was initially controversial.[21][18] The first intramembrane protease to be experimentally identified was site-2 protease in 1997.[9]

References

  1. ^ a b 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. ^ a b c d e f Kühnle, Nathalie; Dederer, Verena; Lemberg, Marius K. (15 August 2019). "Intramembrane proteolysis at a glance: from signalling to protein degradation". Journal of Cell Science. 132 (16): jcs217745. doi:10.1242/jcs.217745.
  6. ^ 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. doi:10.1186/gb-2003-4-3-r19. PMC 153459. PMID 12620104.
  7. ^ 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.
  8. ^ Wolfe, M. S. (3 February 2009). "Intramembrane-cleaving Proteases". Journal of Biological Chemistry. 284 (21): 13969–13973. doi:10.1074/jbc.R800039200. PMC 2682844. PMID 19189971.
  9. ^ a b 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ Hampton, Shahienaz E.; Dore, Timothy M.; Schmidt, Walter K. (4 March 2018). "Rce1: mechanism and inhibition". Critical Reviews in Biochemistry and Molecular Biology. 53 (2): 157–174. doi:10.1080/10409238.2018.1431606. PMC 5874806.
  16. ^ Manolaridis, Ioannis; Kulkarni, Kiran; Dodd, Roger B.; Ogasawara, Satoshi; Zhang, Ziguo; Bineva, Ganka; O’Reilly, Nicola; Hanrahan, Sarah J.; Thompson, Andrew J.; Cronin, Nora; Iwata, So; Barford, David (December 2013). "Mechanism of farnesylated CAAX protein processing by the intramembrane protease Rce1". Nature. 504 (7479): 301–305. doi:10.1038/nature12754. PMC 3864837. PMID 24291792.
  17. ^ a b c d Sun, Linfeng; Li, Xiaochun; Shi, Yigong (April 2016). "Structural biology of intramembrane proteases: mechanistic insights from rhomboid and S2P to γ-secretase". Current Opinion in Structural Biology. 37: 97–107. doi:10.1016/j.sbi.2015.12.008.
  18. ^ a b c d Beard, Hester A.; Barniol-Xicota, Marta; Yang, Jian; Verhelst, Steven H. L. (15 November 2019). "Discovery of Cellular Roles of Intramembrane Proteases". ACS Chemical Biology. 14 (11): 2372–2388. doi:10.1021/acschembio.9b00404.
  19. ^ a b Sanders, Charles R; Hutchison, James M (August 2018). "Membrane properties that shape the evolution of membrane enzymes". Current Opinion in Structural Biology. 51: 80–91. doi:10.1016/j.sbi.2018.03.013. PMC 6158105. PMID 29597094.
  20. ^ Güner G, Lichtenthaler SF (September 2020). "The substrate repertoire of γ-secretase/presenilin". Seminars in Cell & Developmental Biology. 105: 27–42. doi:10.1016/j.semcdb.2020.05.019. PMID 32616437.
  21. ^ a b Paschkowsky, Sandra; Hsiao, Jacqueline Melissa; Young, Jason C.; Munter, Lisa Marie (June 2019). "The discovery of proteases and intramembrane proteolysis". Biochemistry and Cell Biology. 97 (3): 265–269. doi:10.1139/bcb-2018-0186.
  22. ^ Selkoe, Dennis J. (August 1996). "Amyloid β-Protein and the Genetics of Alzheimer's Disease". Journal of Biological Chemistry. 271 (31): 18295–18298. doi:10.1074/jbc.271.31.18295.
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