The Eukaryote Linear Motif resource for Functional Sites in Proteins
Accession:
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)
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)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P54259 ATN1
ATN1_HUMAN
106 110 PQSPSDLDSLDGRSLNDDGS TP 4 Homo sapiens (Human)
P06400 RB1
RB_HUMAN
883 887 RFDIEGSDEADGSKHLPGES TP 3 Homo sapiens (Human)
1 
P06400 RB1
RB_HUMAN
346 350 HDKTLQTDSIDSFETQRTPR TP 3 Homo sapiens (Human)
1 
Q13177 PAK2
PAK2_HUMAN
209 213 VPAPVGDSHVDGAAKSLDKQ TP 3 Homo sapiens (Human)
1 
Q05655 PRKCD
KPCD_HUMAN
326 330 KTGVAGEDMQDNSGTYGKIW TP 3 Homo sapiens (Human)
1 
1 
P11473 VDR
VDR_HUMAN
195 199 DHCITSSDMMDSSSFSNLDL TP 3 Homo sapiens (Human)
1 
O35254 Gorasp1
GORS1_RAT
317 321 FLDVSGMSLLDSNNTSVCPS TP 5 Rattus norvegicus (Norway rat)
1 
O35254 Gorasp1
GORS1_RAT
372 376 SGSEFEISFPDSPGSQAQVD TP 5 Rattus norvegicus (Norway rat)
1 
O35254 Gorasp1
GORS1_RAT
390 394 VDHLPRLTLPDGLTSAASPE TP 5 Rattus norvegicus (Norway rat)
1 
Q13464 ROCK1
ROCK1_HUMAN
1110 1114 VASFPSADETDGNLPESRIE TP 3 Homo sapiens (Human)
1 
P32926 DSG3
DSG3_HUMAN
778 782 STGGTNKDYADGAISMNFLD TP 4 Homo sapiens (Human)
1 
Q02413 DSG1
DSG1_HUMAN
885 889 HGMLEMPDLRDGSNVIVTER TP 3 Homo sapiens (Human)
1 
P12830 CDH1
CADH1_HUMAN
747 751 PLLPPEDDTRDNVYYYDEEG TP 4 Homo sapiens (Human)
1 
P55212 CASP6
CASP6_HUMAN
176 180 DVPVIPLDVVDNQTEKLDTN TP 3 Homo sapiens (Human)
1 
P55212 CASP6
CASP6_HUMAN
190 194 EKLDTNITEVDAASVYTLPA TP 3 Homo sapiens (Human)
1 
P55212 CASP6
CASP6_HUMAN
20 24 AGGEENMTETDAFYKREMFD TP 3 Homo sapiens (Human)
1 
P09874 PARP1
PARP1_HUMAN
211 215 SEGKRKGDEVDGVDEVAKKK TP 3 Homo sapiens (Human)
1 
P08621 SNRNP70
RU17_HUMAN
338 342 PPGELGPDGPDGPEEKGRDR TP 2 Homo sapiens (Human)
1 
P78527 PRKDC
PRKDC_HUMAN
2710 2714 KRLGLPGDEVDNKVKGAAGR TP 3 Homo sapiens (Human)
1 
Q12772 SREBF2
SRBP2_HUMAN
465 469 LDDAKVKDEPDSPPVALGMV TP 4 Homo sapiens (Human)
1 
P36956 SREBF1
SRBP1_HUMAN
457 461 SGGSGSDSEPDSPVFEDSKA TP 4 Homo sapiens (Human)
1 
Q13813 SPTAN1
SPTA2_HUMAN
1182 1186 VYGMMPRDETDSKTASPWKS TP 4 Homo sapiens (Human)
1 
Q13813 SPTAN1
SPTA2_HUMAN
1475 1479 LNTEDKGDSLDSVEALIKKH TP 4 Homo sapiens (Human)
1 
Q01082 SPTBN1
SPTB2_HUMAN
1454 1458 SQEGKSTDEVDSKRLTVQTK TP 4 Homo sapiens (Human)
1 
P42858 HTT
HD_HUMAN
547 551 VPSDPAMDLNDGTQASSPIS TP 3 Homo sapiens (Human)
1 
O54824 Il16
IL16_MOUSE
1201 1205 EATHDLNSSTDSAASASAAS TP 2 Mus musculus (House mouse)
1 
Q63767 Bcar1
BCAR1_RAT
413 417 VPPSVSKDVPDGPLLREETY TP 4 Rattus norvegicus (Norway rat)
1 
P55211 CASP9
CASP9_HUMAN
327 331 QEGLRTFDQLDAISSLPTPS TP 3 Homo sapiens (Human)
1 
Q9HAW4 CLSPN
CLSPN_HUMAN
22 26 DPNVISQEEADSPSDSGQGS TP 4 Homo sapiens (Human)
1 
Q9UQF2 MAPK8IP1
JIP1_HUMAN
95 99 QAEMLQMDLIDATGDTPGAE TP 3 Homo sapiens (Human)
1 
Q9UQF2 MAPK8IP1
JIP1_HUMAN
405 409 PCFGDYSDESDSATVYDNCA TP 3 Homo sapiens (Human)
1 
Q7KZF4 SND1
SND1_HUMAN
812 816 QDDDARTDAVDSVVRDIQNT TP 4 Homo sapiens (Human)
1 
Q99741 CDC6
CDC6_HUMAN
439 443 IHISQVISEVDGNRMTLSQE TP 3 Homo sapiens (Human)
P60484 PTEN
PTEN_HUMAN
381 385 PDHYRYSDTTDSDPENEPFD TP 2 Homo sapiens (Human)
1 
P54259 ATN1
ATN1_HUMAN
103 107 LPRPQSPSDLDSLDGRSLND TP 4 Homo sapiens (Human)
1 
Q13188 STK3
STK3_HUMAN
319 323 EEENSDEDELDSHTMVKTSV TP 3 Homo sapiens (Human)
1 
Q13043 STK4
STK4_HUMAN
323 327 DEENSEEDEMDSGTMVRAVG TP 6 Homo sapiens (Human)
1 
Q63767 Bcar1
BCAR1_RAT
745 749 PPKFTSQDSPDGQYENSEGG TP 4 Rattus norvegicus (Norway rat)
1 
P52566 ARHGDIB
GDIR2_HUMAN
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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