Caspase 3

Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the CASP3 gene. CASP3 orthologs [4] have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

CASP3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1CP3, 1GFW, 1I3O, 1NME, 1NMQ, 1NMS, 1PAU, 1QX3, 1RE1, 1RHJ, 1RHK, 1RHM, 1RHQ, 1RHR, 1RHU, 2C1E, 2C2K, 2C2M, 2C2O, 2CDR, 2CJX, 2CJY, 2CNK, 2CNL, 2CNN, 2CNO, 2DKO, 2H5I, 2H5J, 2H65, 2J30, 2J31, 2J32, 2J33, 2XYG, 2XYH, 2XYP, 2XZD, 2XZT, 2Y0B, 3DEH, 3DEI, 3DEJ, 3DEK, 3EDQ, 3GJQ, 3GJR, 3GJS, 3GJT, 3H0E, 3ITN, 3KJF, 3PCX, 3PD0, 3PD1, 4DCJ, 4DCO, 4DCP, 4EHA, 4EHD, 4EHF, 4EHH, 4EHK, 4EHL, 4EHN, 4JJE, 4JQY, 4JQZ, 4JR0, 4PRY, 4PS0, 4QTX, 4QTY, 4QU0, 4QU5, 4QU8, 4QU9, 4QUA, 4QUB, 4QUD, 4QUE, 4QUG, 4QUH, 4QUI, 4QUJ, 4QUL, 5IC4
Identifiers
Aliases	CASP3, CPP32, CPP32B, SCA-1, caspase 3
External IDs	OMIM: 600636 MGI: 107739 HomoloGene: 37912 GeneCards: CASP3
Gene location (Mouse) Chr. Chromosome 8 (mouse)[1] Band 8 B1.1|8 26.39 cM Start 46,617,291 bp[1] End 46,639,689 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • cysteine-type peptidase activity • peptidase activity • GO:0001948 protein binding • phospholipase A2 activator activity • cyclin-dependent protein serine/threonine kinase inhibitor activity • cysteine-type endopeptidase activity involved in apoptotic process • cysteine-type endopeptidase activity involved in execution phase of apoptosis • cysteine-type endopeptidase activity • hydrolase activity • cysteine-type endopeptidase activator activity involved in apoptotic process • aspartic-type endopeptidase activity • protease binding • death receptor binding • GO:0032403 macromolecular complex binding • cysteine-type endopeptidase activity involved in apoptotic signaling pathway Cellular component • cytoplasm • cytosol • nucleoplasm • death-inducing signaling complex • membrane raft • cell nucleus • neuronal cell body Biological process • cellular response to organic substance • neuron apoptotic process • cell fate commitment • response to estradiol • GO:0007243 intracellular signal transduction • response to hypoxia • response to amino acid • apoptotic DNA fragmentation • response to organic cyclic compound • negative regulation of cyclin-dependent protein serine/threonine kinase activity • response to antibiotic • platelet formation • protein processing • response to nicotine • response to metal ion • negative regulation of cell cycle • wound healing • response to glucocorticoid • cellular response to organic cyclic compound • B cell homeostasis • negative regulation of apoptotic process • sensory perception of sound • response to glucose • response to organic substance • Hippo signaling pathway • glial cell apoptotic process • keratinocyte differentiation • proteolysis • cellular response to DNA damage stimulus • T cell homeostasis • response to tumor necrosis factor • negative regulation of activated T cell proliferation • heart development • response to lipopolysaccharide • positive regulation of neuron apoptotic process • response to wounding • neuron differentiation • extrinsic apoptotic signaling pathway in absence of ligand • learning or memory • positive regulation of apoptotic process • erythrocyte differentiation • apoptotic signaling pathway • negative regulation of B cell proliferation • response to cobalt ion • hippocampus development • response to UV • response to X-ray • response to drug • response to hydrogen peroxide • regulation of macroautophagy • neurotrophin TRK receptor signaling pathway • execution phase of apoptosis • intrinsic apoptotic signaling pathway in response to osmotic stress • cellular response to staurosporine • apoptotic process • cytokine-mediated signaling pathway • activation of cysteine-type endopeptidase activity involved in apoptotic process • GO:0048554 positive regulation of catalytic activity • luteolysis • axonal fasciculation • striated muscle cell differentiation • leukocyte apoptotic process • regulation of protein stability • positive regulation of amyloid-beta formation • anterior neural tube closure Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	836	12367
Ensembl	ENSG00000164305	ENSMUSG00000031628
UniProt	P42574	P70677
RefSeq (mRNA)	NM_004346 NM_032991	NM_009810 NM_001284409
RefSeq (protein)	NP_004337 NP_116786 NP_001341706 NP_001341708 NP_001341709 NP_001341710 NP_001341711 NP_001341712 NP_001341713	NP_001271338 NP_033940
Location (UCSC)	n/a	Chr 8: 46.62 – 46.64 Mb
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

The CASP3 protein is a member of the cysteine-aspartic acid protease (caspase) family.[5] Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes that undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein cleaves and activates caspases 6 and 7; and the protein itself is processed and activated by caspases 8, 9, and 10. It is the predominant caspase involved in the cleavage of amyloid-beta 4A precursor protein, which is associated with neuronal death in Alzheimer's disease.[6] Alternative splicing of this gene results in two transcript variants that encode the same protein.[7]

Signaling pathway of TNF-R1. Dashed grey lines represent multiple steps

Pathways leading to caspase 3 activation.[8]

Caspase-3 shares many of the typical characteristics common to all currently-known caspases. For example, its active site contains a cysteine residue (Cys-163) and histidine residue (His-121) that stabilize the peptide bond cleavage of a protein sequence to the carboxy-terminal side of an aspartic acid when it is part of a particular 4-amino acid sequence.[9][10] This specificity allows caspases to be incredibly selective, with a 20,000-fold preference for aspartic acid over glutamic acid.[11] A key feature of caspases in the cell is that they are present as zymogens, termed procaspases, which are inactive until a biochemical change causes their activation. Each procaspase has an N-terminal large subunit of about 20 kDa followed by a smaller subunit of about 10 kDa, called p20 and p10, respectively.[12]

Substrate specificity

Under normal circumstances, caspases recognize tetra-peptide sequences on their substrates and hydrolyze peptide bonds after aspartic acid residues. Caspase 3 and caspase 7 share similar substrate specificity by recognizing tetra-peptide motif Asp-x-x-Asp.[13] The C-terminal Asp is absolutely required while variations at other three positions can be tolerated.[14] Caspase substrate specificity has been widely used in caspase based inhibitor and drug design.[15]

Structure

Caspase-3, in particular, (also known as CPP32/Yama/apopain)[16][17][18] is formed from a 32 kDa zymogen that is cleaved into 17 kDa and 12 kDa subunits. When the procaspase is cleaved at a particular residue, the active heterotetramer can then be formed by hydrophobic interactions, causing four anti-parallel beta-sheets from p17 and two from p12 to come together to make a heterodimer, which in turn interacts with another heterodimer to form the full 12-stranded beta-sheet structure surrounded by alpha-helices that is unique to caspases.[12][19] When the heterodimers align head-to-tail with each other, an active site is positioned at each end of the molecule formed by residues from both participating subunits, though the necessary Cys-163 and His-121 residues are found on the p17 (larger) subunit.[19]

The p12 (pink) and p17 (light blue) subunits of caspase-3 with the beta-sheet structures of each in red and blue, respectively; image generated in Pymol from 1rhm.pdb

Mechanism

The catalytic site of caspase-3 involves the sulfohydryl group of Cys-163 and the imidazole ring of His-121. His-121 stabilizes the carbonyl group of the key aspartate residue, while Cys-163 attacks to ultimately cleave the peptide bond. Cys-163 and Gly-238 also function to stabilize the tetrahedral transition state of the substrate-enzyme complex through hydrogen bonding.[19] In vitro, caspase-3 has been found to prefer the peptide sequence DEVDG (Asp-Glu-Val-Asp-Gly) with cleavage occurring on the carboxy side of the second aspartic acid residue (between D and G).[11][19][20] Caspase-3 is active over a broad pH range that is slightly higher (more basic) than many of the other executioner caspases. This broad range indicates that caspase-3 will be fully active under normal and apoptotic cell conditions.[21]

Cys-285 (yellow) and His-237 (green and dark blue) in the active site of caspase-3, p12 subunit in pink and p17 subunit in light blue; image generated in Pymol from 1rhr.pdb

Activation

Caspase-3 is activated in the apoptotic cell both by extrinsic (death ligand) and intrinsic (mitochondrial) pathways.[12][22] The zymogen feature of caspase-3 is necessary because if unregulated, caspase activity would kill cells indiscriminately.[23] As an executioner caspase, the caspase-3 zymogen has virtually no activity until it is cleaved by an initiator caspase after apoptotic signaling events have occurred.[24] One such signaling event is the introduction of granzyme B, which can activate initiator caspases, into cells targeted for apoptosis by killer T cells.[25][26] This extrinsic activation then triggers the hallmark caspase cascade characteristic of the apoptotic pathway, in which caspase-3 plays a dominant role.[10] In intrinsic activation, cytochrome c from the mitochondria works in combination with caspase-9, apoptosis-activating factor 1 (Apaf-1), and ATP to process procaspase-3.[20][26][27] These molecules are sufficient to activate caspase-3 in vitro, but other regulatory proteins are necessary in vivo.[27] Mangosteen (Garcinia mangostana) extract has been shown to inhibit the activation of caspase 3 in B-amyloid treated human neuronal cells.[28]

Inhibition

One means of caspase inhibition is through the IAP (inhibitor of apoptosis) protein family, which includes c-IAP1, c-IAP2, XIAP, and ML-IAP.[19] XIAP binds and inhibits initiator caspase-9, which is directly involved in the activation of executioner caspase-3.[27] During the caspase cascade, however, caspase-3 functions to inhibit XIAP activity by cleaving caspase-9 at a specific site, preventing XIAP from being able to bind to inhibit caspase-9 activity.[29]

Interactions

Caspase 3 has been shown to interact with:

• CASP8[30][31]
• NMT2[32]
• CFLAR[33][34]
• DCC[35]
• GroEL[36][37]
• HCLS1[38][39]
• Survivin[40][41]
• TRAF3[42][43]
• XIAP[44][45][46][47][48][49]
• NFE2L2[50]

Biological function

Caspase-3 has been found to be necessary for normal brain development as well as its typical role in apoptosis, where it is responsible for chromatin condensation and DNA fragmentation.[20] Elevated levels of a fragment of Caspase-3, p17, in the bloodstream is a sign of a recent myocardial infarction.[51] It is now being shown that caspase-3 may play a role in embryonic and hematopoietic stem cell differentiation.[52]

See also

• The Proteolysis Map
• Caspase
• PAC-1

References

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Further reading

• Cohen GM (August 1997). "Caspases: the executioners of apoptosis". The Biochemical Journal. 326 (Pt 1): 1–16. doi:10.1042/bj3260001. PMC 1218630. PMID 9337844.
• Roig J, Traugh JA (2001). Cytostatic p21 G protein-activated protein kinase gamma-PAK. Vitamins & Hormones. 62. pp. 167–98. doi:10.1016/S0083-6729(01)62004-1. ISBN 9780127098623. PMID 11345898.
• Zhao LJ, Zhu H (December 2004). "Structure and function of HIV-1 auxiliary regulatory protein Vpr: novel clues to drug design". Current Drug Targets. Immune, Endocrine and Metabolic Disorders. 4 (4): 265–75. doi:10.2174/1568008043339668. PMID 15578977.
• Le Rouzic E, Benichou S (2006). "The Vpr protein from HIV-1: distinct roles along the viral life cycle". Retrovirology. 2 (1): 11. doi:10.1186/1742-4690-2-11. PMC 554975. PMID 15725353.
• Sykes MC, Mowbray AL, Jo H (February 2007). "Reversible glutathiolation of caspase-3 by glutaredoxin as a novel redox signaling mechanism in tumor necrosis factor-alpha-induced cell death". Circulation Research. 100 (2): 152–4. doi:10.1161/01.RES.0000258171.08020.72. PMID 17272816.

External links

• The MEROPS online database for peptidases and their inhibitors: C14.003
• Apoptosis & Caspase 3 – The Proteolysis Map-animation