Accession: | |
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Functional site class: | Caspase cleavage motif |
Functional site description: | The proteases caspases-3 and -7 play an important role in programmed cell death (apoptosis). Cleavage of the caspase substrates results in characteristic morphological features of apoptotic cell death, including membrane blebbing, pyknotic nuclei, cell rounding, and formation of apoptotic vesicles. Caspases recognise their substrates by a cleavage motif. The amino acids of the substrate around the caspase cleavage site are named N- to C-terminal: P4, P3, P2, P1, P-1. The scissile bond between the essential aspartate at P1 and P-1, usually a small amino acid, is cleaved by caspase-3 and -7, whereas positions P4 to P-1 are important for substrate specificity and recognition. |
ELM Description: | The amino acids around the caspase-3 and -7 cleavage site are named N- to C-terminal: P4, P3, P3, P2, P1, P-1. The scissile bond between P1 and P-1 is cleaved by caspase-3 and -7, whereas positions P4 to P-1 are important for substrate specificity and recognition. P1 is always an aspartate (D), while P-1 is usually a small amino acid. Proline (P) as secondary alpha-amino acid is not accepted at P-1. An in vitro kinetic study argues for small amino acids, phenylalanine (F) or tyrosine and no ionic amino acids at P-1 (Stennicke,2000). The regular expression allows small amino acids at P-1. Other residues are still described but data was not valid enough to create an additional regular expression. The backbone of amino acids at P2 and P3 is stabilised by hydrogen (H) bonds allowing caspase-3 and -7 a broad spectrum of amino acids at these positions. At P2 non-polar amino acids (valine (V), leucine (L), P) are preferred because of possible interactions with a hydrophobic pocket. Threonine (T) is also very common. At P3 glutamate (E) is preferred because of an additional H-bond. However other amino acids like serine (S) or L are still common. In the regular expression P3 is not specified, except for the prohibition of P, because caspase-3 and -7 accept a variety of amino acids at P3. D is strongly preferred at P4 due to strong H-bond interactions, followed by S, T, and E. Crystal structures with pentapeptides argue for a preference for hydrophobic residues at P5 because of hydrophobic interactions with two F residues in case of caspase-3. This site is missing in caspase-7 (Fu,2008). The regular expression does not include P5 because caspase-3 cleaves also substrates with non-hydrophobic residues at P5. Nevertheless a hydrophobic residue at P5 is a hint that the protein is rather a caspase-3 substrate then a caspase-7 one. Based on the observed variations at P4-P2, the regular expression will on the one hand produce false positives and on the other hand not match all described cleavage sites. |
Pattern: | [DSTE][^P][^DEWHFYC]D[GSAN] |
Pattern Probability: | 0.0030937 |
Present in taxon: | Metazoa |
Interaction Domain: |
Peptidase_C14 (PF00656)
Caspase domain
(Stochiometry: 1 : 1)
|
Abstract |
Cysteinyl aspartate specific proteases (caspases) play an important role in development, differentiation, apoptosis and inflammation in metazoa. The 12 known human caspases, members of peptidase family C14, can be classified in 4 groups based on their function and the length of their prodomain. Group I caspases are inflammatory caspases with a large prodomain and includes caspase-1, -4, -5, and -12. Caspases-2, -5, -8, -9, and -10 belong to group II and have also a large prodomain, but initiate apoptosis. Caspase-3, -6, and -7 constitute group III and are effector caspases with a short (20-30 aa) prodomain that execute the apoptotic program by cleavage of various proteins. Caspase-14 is involved in keratinocyte differentiation (Lavrik,2005, Pop,2009). A general characteristic of caspases is their high specificity to cleave C-terminal after aspartate (Stennicke,2000). This primary specificity for aspartate is unique to the granzyme B and caspase families of proteases (Harris,2000). The amino acids N-terminal of the aspartate, mainly the first four, determine the caspase's specificity. Under normal conditions caspases are present as inactive enzyme precursors (zymogens), the procaspases. They consist of an N-terminal prodomain, the large subunit (p20), an optional linker sequence, and the small subunit (p10). The structure of all caspases is a heterotetramer formed by head-tail organised heterodimers that are composed of the small and the large subunit (Fu,2008, Chai,2001). The caspases' substrate is stabilized by amino acids from both subunits, whereas the catalytic dyad is localised within the large subunit and consists of a cysteine and a histidine (Wilson,1994). In vivo active initiator caspase-8, -9, and -10 and the lymphocyte-specific serine protease granzyme B perform proteolytic activation of the caspase-3 and -7 zymogen dimer by cleavage of the prodomain and the inhibiting linker. This activation can occur by two different mechanisms: the extrinsic and the intrinsic pathway. In the extrinsic or death receptor-mediated pathway death receptor ligands induce the oligomerization of death receptor (CD95 or TRAIL-R1/R2) resulting in the formation of the death-inducing signalling complex (DISC). Caspase-8 and -10 are activated by DISC and cleave caspase-3 and -7. The intrinsic or mitochondria-mediated pathway is induced by stimuli such as DNA damage, cytotoxic stress, and heat shock leading to the release of cytochrome C from the mitochondria and the formation of the apoptosome. After its activation by the apoptosome caspase-9 processes caspase-3 and -7 (Jiang,2000). Executor caspases-3 and -7 cleave a variety of downstream proteins resulting in membrane blebbing, pyknotic nuclei, cell rounding, formation of apoptotic vesicles, and finally in apoptotic cell death. Non-apoptotic activities of caspases including involvement in immune response (Zhang,1998), proliferation (Woo,2003), differentiation (Zermati,2001, Carlile,2004), and cell motility (Barnhart,2004) are also described. However little is known about this, particularly the control and regulation of specific caspase cleavage. Regulation of caspases' non-apoptotic activities presumably occurs by post-translational modification of the caspases and/or the substrates, subcellular compartmentalisation of caspases, protection of potential substrates by scaffold proteins or protein complexes, activation of anti-apoptotic factors, and recruitment of antagonistic proteins at the level of caspase activation complexes (Launay,2005, Yi,2009). Due to their ability to induce apoptotic cell death, the activation of caspases and active caspases are modulated and/or inhibited by a number of regulatory mechanisms. The activation of caspase-8 at the DISC can be modulated by cellular FLICE-inhibiting protein (cFLIP), a member of the DISC (11713262). Inhibition of apoptosis protein (IAP) family inhibits the enzymatic activities of caspases using baculoviral IAP repeats (LIG_BIR_II_1, LIG_BIR_III_1, LIG_BIR_III_2, LIG_BIR_III_3, LIG_BIR_III_4) (Deveraux,1999). The most prominent IAP XIAP inhibits caspase-3, -7 and -9. It interacts with the N-terminal of the small caspase subunit and shields the catalytic side of caspase-3 and -7 by reverse binding (Eckelman,2006). Two other natural, viral pan-caspase inhibitors are known: p35 (Xu,2001) and CrmA (Renatus,2000). |
9 GO-Terms:
41 Instances for CLV_C14_Caspase3-7
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Please cite:
The Eukaryotic Linear Motif resource: 2022 release.
(PMID:34718738)
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement