Intramembrane protease

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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]

Contents

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]

Related Research Articles

<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.

<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.

<span class="mw-page-title-main">Amyloid-beta precursor protein secretase</span>

Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane.

<span class="mw-page-title-main">Beta-secretase 1</span> Enzyme

Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is encoded by the BACE1 gene. Expression of BACE1 is observed mainly in neurons.

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> Type of protein

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">Nicastrin</span>

Nicastrin, also known as NCSTN, is a protein that in humans is encoded by the NCSTN gene.

APH-1 is a protein gene product originally identified in the Notch signaling pathway in Caenorhabditis elegans as a regulator of the cell-surface localization of nicastrin. APH-1 homologs in other organisms, including humans, have since been identified as components of the gamma secretase complex along with the catalytic subunit presenilin and the regulatory subunits nicastrin and PEN-2. The gamma-secretase complex is a multimeric protease responsible for the intramembrane proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein (APP). Gamma-secretase cleavage of APP is one of two proteolytic steps required to generate the peptide known as amyloid beta, whose misfolded form is implicated in the causation of Alzheimer's disease. All of the components of the gamma-secretase complex undergo extensive post-translational modification, especially proteolytic activation; APH-1 and PEN-2 are regarded as regulators of the maturation process of the catalytic component presenilin. APH-1 contains a conserved alpha helix interaction motif glycine-X-X-X-glycine (GXXXG) that is essential to both assembly of the gamma secretase complex and to the maturation of the components.

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

PSENEN, formally PEN-2, is a protein that is a regulatory component of the gamma secretase complex, a protease complex responsible for proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein (APP). The gamma secretase complex consists of PEN-2, APH-1, nicastrin, and the catalytic subunit presenilin. PEN-2 is a 101-amino acid integral membrane protein likely with a topology such that both the N-terminus and the C-terminus face first the lumen of the endoplasmic reticulum and later the extracellular environment. Biochemical studies have shown that a conserved sequence motif D-Y-L-S-F at the C-terminus, as well as the overall length of the C-terminal tail, is required for the formation of an active gamma secretase complex.

<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.

<span class="mw-page-title-main">PSEN2</span> Protein-coding gene in the species Homo sapiens

Presenilin-2 is a protein that is encoded by the PSEN2 gene.

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">HM13</span> Protein-coding gene in the species Homo sapiens

Minor histocompatibility antigen H13 is a protein that in humans is encoded by the HM13 gene.

<span class="mw-page-title-main">SPPL2B</span> Protein-coding gene in the species Homo sapiens

Signal peptide peptidase-like 2B, also known as SPPL2B, is a human gene.

<span class="mw-page-title-main">SPPL2A</span> Protein-coding gene in the species Homo sapiens

Signal peptide peptidase-like 2A, also known as SPPL2A, is a human gene.

<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">Rhomboid protease</span>

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. 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.

<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.

References

  1. 1 2 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. 1 2 3 4 5 6 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. 1 2 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 . PMID   29424242.
  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. 1 2 3 4 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. 1 2 3 4 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. 1 2 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. 1 2 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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