The Eukaryote Linear Motif resource for Functional Sites in Proteins
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 with this model: CLV_C14_Caspase3-7 
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: 0.0035648
Present in taxon: Metazoa
Interaction Domain:
Peptidase_C14 (PF00656) Caspase domain (Stochiometry: 1 : 1)
o See 39 Instances for CLV_C14_Caspase3-7
o 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).
o 16 selected references:

o 9 GO-Terms:

o 39 Instances for CLV_C14_Caspase3-7
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Protein NameGene NameStartEndSubsequenceLogic#Ev.OrganismNotes
ATN1_HUMAN ATN1 106 110 PQSPSDLDSLDGRSLNDDGS TP 4 Homo sapiens (Human)
RB_HUMAN RB1 883 887 RFDIEGSDEADGSKHLPGES TP 3 Homo sapiens (Human)
1 
RB_HUMAN RB1 346 350 HDKTLQTDSIDSFETQRTPR TP 3 Homo sapiens (Human)
1 
PAK2_HUMAN PAK2 209 213 VPAPVGDSHVDGAAKSLDKQ TP 3 Homo sapiens (Human)
1 
KPCD_HUMAN PRKCD 326 330 KTGVAGEDMQDNSGTYGKIW TP 3 Homo sapiens (Human)
1 
1 
VDR_HUMAN VDR 195 199 DHCITSSDMMDSSSFSNLDL TP 3 Homo sapiens (Human)
1 
GORS1_RAT Gorasp1 317 321 FLDVSGMSLLDSNNTSVCPS TP 5 Rattus norvegicus (Norway rat)
1 
GORS1_RAT Gorasp1 372 376 SGSEFEISFPDSPGSQAQVD TP 5 Rattus norvegicus (Norway rat)
1 
GORS1_RAT Gorasp1 390 394 VDHLPRLTLPDGLTSAASPE TP 5 Rattus norvegicus (Norway rat)
1 
ROCK1_HUMAN ROCK1 1110 1114 VASFPSADETDGNLPESRIE TP 3 Homo sapiens (Human)
1 
DSG3_HUMAN DSG3 778 782 STGGTNKDYADGAISMNFLD TP 4 Homo sapiens (Human)
1 
DSG1_HUMAN DSG1 885 889 HGMLEMPDLRDGSNVIVTER TP 3 Homo sapiens (Human)
1 
CADH1_HUMAN CDH1 747 751 PLLPPEDDTRDNVYYYDEEG TP 4 Homo sapiens (Human)
1 
CASP6_HUMAN CASP6 176 180 DVPVIPLDVVDNQTEKLDTN TP 3 Homo sapiens (Human)
1 
CASP6_HUMAN CASP6 190 194 EKLDTNITEVDAASVYTLPA TP 3 Homo sapiens (Human)
1 
CASP6_HUMAN CASP6 20 24 AGGEENMTETDAFYKREMFD TP 3 Homo sapiens (Human)
1 
PARP1_HUMAN PARP1 211 215 SEGKRKGDEVDGVDEVAKKK TP 3 Homo sapiens (Human)
1 
RU17_HUMAN SNRNP70 338 342 PPGELGPDGPDGPEEKGRDR TP 2 Homo sapiens (Human)
1 
PRKDC_HUMAN PRKDC 2710 2714 KRLGLPGDEVDNKVKGAAGR TP 3 Homo sapiens (Human)
1 
SRBP2_HUMAN SREBF2 465 469 LDDAKVKDEPDSPPVALGMV TP 4 Homo sapiens (Human)
1 
SRBP1_HUMAN SREBF1 457 461 SGGSGSDSEPDSPVFEDSKA TP 4 Homo sapiens (Human)
1 
SPTA2_HUMAN SPTAN1 1182 1186 VYGMMPRDETDSKTASPWKS TP 4 Homo sapiens (Human)
1 
SPTA2_HUMAN SPTAN1 1475 1479 LNTEDKGDSLDSVEALIKKH TP 4 Homo sapiens (Human)
1 
SPTB2_HUMAN SPTBN1 1454 1458 SQEGKSTDEVDSKRLTVQTK TP 4 Homo sapiens (Human)
1 
HD_HUMAN HTT 547 551 VPSDPAMDLNDGTQASSPIS TP 3 Homo sapiens (Human)
1 
IL16_MOUSE Il16 1201 1205 EATHDLNSSTDSAASASAAS TP 2 Mus musculus (House mouse)
1 
BCAR1_RAT Bcar1 413 417 VPPSVSKDVPDGPLLREETY TP 4 Rattus norvegicus (Norway rat)
1 
CASP9_HUMAN CASP9 327 331 QEGLRTFDQLDAISSLPTPS TP 3 Homo sapiens (Human)
1 
CLSPN_HUMAN CLSPN 22 26 DPNVISQEEADSPSDSGQGS TP 4 Homo sapiens (Human)
1 
JIP1_HUMAN MAPK8IP1 95 99 QAEMLQMDLIDATGDTPGAE TP 3 Homo sapiens (Human)
1 
JIP1_HUMAN MAPK8IP1 405 409 PCFGDYSDESDSATVYDNCA TP 3 Homo sapiens (Human)
1 
SND1_HUMAN SND1 812 816 QDDDARTDAVDSVVRDIQNT TP 4 Homo sapiens (Human)
1 
CDC6_HUMAN CDC6 439 443 IHISQVISEVDGNRMTLSQE TP 3 Homo sapiens (Human)
PTEN_HUMAN PTEN 381 385 PDHYRYSDTTDSDPENEPFD TP 2 Homo sapiens (Human)
1 
ATN1_HUMAN ATN1 103 107 LPRPQSPSDLDSLDGRSLND TP 4 Homo sapiens (Human)
1 
STK3_HUMAN STK3 319 323 EEENSDEDELDSHTMVKTSV TP 3 Homo sapiens (Human)
1 
STK4_HUMAN STK4 323 327 DEENSEEDEMDSGTMVRAVG TP 6 Homo sapiens (Human)
1 
BCAR1_RAT Bcar1 745 749 PPKFTSQDSPDGQYENSEGG TP 4 Rattus norvegicus (Norway rat)
1 
GDIR2_HUMAN ARHGDIB 16 20 HVEEDDDDELDSKLNYKPPP TP 4 Homo sapiens (Human)
1 
Please cite: The Eukaryotic Linear Motif Resource ELM: 10 Years and Counting (PMID:24214962)

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