캐스페이스 3

3. 구조

캐스페이스 3(CPP32/Yama/apopain이라고도 함)은^{[108][109][110]} 32 kDa 크기의 전구체(pro-caspase 3) 형태로 생성되며, 활성화 과정에서 17 kDa (p17) 및 12 kDa (p12) 소단위체로 절단된다. p17과 p12 소단위체는 각각 4개와 2개의 역평행 베타 시트 구조를 가지며, 이들이 결합하여 이형이량체(heterodimer)를 형성한다. 두 개의 이형이량체가 다시 결합하여 활성형 사량체(heterotetramer)를 형성하며, 이는 알파 나선으로 둘러싸인 12가닥 베타 시트 구조를 이룬다. 활성 부위는 각 이형이량체의 경계면에 위치하며, Cys-163과 His-121 잔기가 촉매 반응에 중요한 역할을 한다.^[16]

4. 메커니즘

캐스페이스 3의 촉매 부위는 Cys-163의 티올기(-SH)와 His-121의 이미다졸 고리를 포함한다. His-121은 핵심 아스파르트산 잔기의 카보닐기를 안정화시키는 반면, Cys-163은 펩타이드 결합을 절단하기 위해 공격한다. Cys-163과 Gly-238은 수소 결합을 통해 기질-효소 복합체의 사면체 전이 상태를 안정화시키는 기능도 한다.^[121] 시험관 내 실험(In vitro)에서 캐스페이스 3은 DEVDG(Asp-Glu-Val-Asp-Gly) 펩타이드 서열에서 두 번째 아스파르트산 잔기(D와 G 사이)의 카르복시 말단에서 절단이 일어나는 것을 선호하는 것으로 밝혀졌다.^{[111][121][124]} 캐스페이스 3는 다른 많은 실행자(executioner) 캐스페이스보다 약간 더 염기성인 넓은 pH 범위에서 활성을 띤다. 이러한 넓은 활성 pH 범위는 캐스페이스 3가 정상 세포 및 세포 사멸 조건에서 모두 완전히 활성화됨을 나타낸다.^[112]

5. 활성화

캐스페이스 3는 외인성 경로와 내인성 경로를 통해 세포자살에서 활성화된다.^[113][114] 캐스페이스 3의 지모겐 기능은 조절되지 않으면 캐스페이스 활성이 무차별적으로 세포를 죽일 것이기 때문에 반드시 필요하다.^[115] 실행자 캐스페이스로서 캐스페이스 3 지모겐은 세포사멸 신호 이벤트가 발생한 후 개시자 캐스페이스에 의해 절단될 때까지 사실상 활동이 없다.^[116]

• 외인성 경로: 세포 독성 T 세포에 의한 세포사멸을 목표로 하는 세포로 그랜자임 B를 도입하여 개시자 캐스페이스를 활성화한다.^[117][118] 이 경로는 캐스페이스 3가 지배적인 역할을 하는 세포사멸 경로의 특징인 캐스페이스 신호 전달(caspase cascade)을 유발한다.^[119]
• 내인성 경로: 미토콘드리아의 사이토크롬 c는 캐스페이스 9, 세포사멸 활성화 인자 1 (Apaf-1) 및 ATP와 함께 작용하여 프로캐스페이스 3를 처리한다.^{[124][118][122]} 시험관 내에서는 이들 분자들이 캐스페이스 3를 활성화하기에 충분하지만, 생체 내에서는 다른 조절 단백질이 필요하다.^[122][120]

6. 억제

캐스페이스 3의 활성은 세포사멸 억제 단백질 (Inhibitor of Apoptosis Proteins, IAPs) 계열에 의해 조절된다.^{[121][16][65]} XIAP는 개시 캐스페이스 9에 결합하여 억제하는데, 캐스페이스 9는 실행자 캐스페이스 3의 활성화에 직접 관여한다.^{[122][24][73]} 그러나 캐스페이스 신호 전달 과정에서 캐스페이스 3는 특정 부위에서 캐스페이스 9를 절단하여 XIAP 활성을 억제함으로써 XIAP가 캐스페이스 9 활성을 억제하지 못하도록 한다.^{[123][26][74]}

망고스틴(''Garcinia mangostana'') 추출물은 아밀로이드 베타로 처리된 인간 신경 세포에서 카스파제-3의 활성화를 억제하는 것으로 나타났다.^[75]

7. 생물학적 기능

캐스페이스 3는 염색질 응축 및 DNA 단편화를 담당하는 세포사멸에서의 전형적인 역할뿐만 아니라 정상적인 뇌 발달에도 필요한 것으로 밝혀졌다.^[124] 혈류에서 캐스페이스 3, 특히 p17 조각의 수치 상승은 심근 경색의 징후로 밝혀졌다.^[125] 또한 캐스페이스 3가 배아 및 조혈 줄기세포 분화에 역할을 할 수 있다는 것도 밝혀지고 있다.^[126]

망고스틴(`Garcinia mangostana`) 추출물은 B-아밀로이드로 처리된 인간 신경 세포에서 캐스페이스 3의 활성화를 억제하는 것으로 나타났다.^[25]

8. 상호작용

Caspase-3(CPP32/Yama/apopain이라고도 함)^[13][14][15]는 32 kDa 자이모겐으로부터 형성되며, 17 kDa와 12 kDa의 서브유닛으로 절단된다. 프로카스파제가 특정 잔기에서 절단되면, 활성 헤테로테트라머는 소수성 상호 작용에 의해 형성될 수 있다. p17에서 4개의 역평행 베타 시트와 p12에서 2개가 함께 모여 카스파제에 고유한 알파 나선으로 둘러싸인 전체 12 가닥 구조를 형성한다.^[9][16] 헤테로다이머가 서로 머리에서 꼬리로 정렬되면, 필요한 Cys-163 및 His-121 잔기는 p17 (더 큰) 서브유닛에서 발견되지만, 활성 부위는 두 참여 서브유닛의 잔기로 형성된 분자의 각 끝에 위치한다.^[16]

8. 1. 상호작용 단백질 목록

참조

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_[56] 논문 Zinc is a potent inhibitor of the apoptotic protease, caspase-3. A novel target for zinc in the inhibition of apoptosis 1997-07
_[57] 논문 Internally quenched fluorescent peptide substrates disclose the subsite preferences of human caspases 1, 3, 6, 7 and 8 2000-09
_[58] 논문 Caspases: opening the boxes and interpreting the arrows 2002-01
_[59] 논문 Plasticity of S2-S4 specificity pockets of executioner caspase-7 revealed by structural and kinetic analysis 2007-09
_[60] 논문 Structural and kinetic analysis of caspase-3 reveals role for s5 binding site in substrate recognition 2006-07
_[61] 논문 Caspases: structure-guided design of drugs to control cell death 2008-10
_[62] 논문 CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme 1994-12
_[63] 논문 Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase 1995-06
_[64] 논문 Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis 1995-07
_[65] 논문 Caspases: pharmacological manipulation of cell death 2005-10
_[66] 논문 Emerging roles of caspase-3 in apoptosis 1999-02
_[67] 논문 Biochemical characteristics of caspases-3, -6, -7, and -8 1997-10
_[68] 논문 Apoptosis and cancer: mutations within caspase genes 2009-08
_[69] 논문 Mechanisms of caspase activation 2003-12
_[70] 논문 A constitutively active and uninhibitable caspase-3 zymogen efficiently induces apoptosis 2009-12
_[71] 논문 Apoptosis: live or die--hard work either way! 2001-09
_[72] 논문 Novel procaspase-3 activating cascade mediated by lysoapoptases and its biological significances in apoptosis
_[73] 논문 Mitochondrial activation of apoptosis 2004-01
_[74] 논문 Caspase 3 attenuates XIAP (X-linked inhibitor of apoptosis protein)-mediated inhibition of caspase 9 2007-07
_[75] 논문 Protective effect of mangosteen extract against beta-amyloid-induced cytotoxicity, oxidative stress and altered proteome in SK-N-SH cells 2010-05
_[76] 논문 Serum caspase-3 p17 fragment is elevated in patients with ST-segment elevation myocardial infarction: a novel observation 2011-01
_[77] 논문 Rehabilitation of a contract killer: caspase-3 directs stem cell differentiation 2008-06
_[78] 논문 Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria 2002-04
_[79] 논문 Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases 1996-12
_[80] 논문 Role of calpain and caspase system in the regulation of N-myristoyltransferase in human colon cancer (Review). 2007-05
_[81] 논문 Casper is a FADD- and caspase-related inducer of apoptosis 1997-06
_[82] 논문 MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death 1997-10
_[83] 논문 The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation 2001-03
_[84] 논문 Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of jurkat cells 1999-04
_[85] 논문 Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis 1999-04
_[86] 논문 Protein kinase CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) induces apoptosis and caspase-dependent degradation of haematopoietic lineage cell-specific protein 1 (HS1) in Jurkat cells 2002-05
_[87] 논문 Caspase-mediated cleavage of actin-binding and SH3-domain-containing proteins cortactin, HS1, and HIP-55 during apoptosis 2001-11
_[88] 논문 IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs 1998-12
_[89] 논문 An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7 2001-01
_[90] 논문 Caspase-mediated cleavage of TRAF3 in FasL-stimulated Jurkat-T cells 2001-03
_[91] 논문 TRAF1 is a substrate of caspases activated during tumor necrosis factor receptor-alpha-induced apoptosis 2001-03
_[92] 논문 Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death 2001-07
_[93] 논문 The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase 3- and caspase 9-interacting sites 2002-04
_[94] 논문 Structural basis for the inhibition of caspase-3 by XIAP 2001-03
_[95] 논문 The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases 1997-12
_[96] 논문 X-linked IAP is a direct inhibitor of cell-death proteases 1997-07
_[97] 논문 X-linked inhibitor of apoptosis protein (XIAP) inhibits caspase-3 and -7 in distinct modes 2001-07
_[98] 논문 Identification of NRF2, a member of the NF-E2 family of transcription factors, as a substrate for caspase-3(-like) proteases 1999-09
_[99] 웹인용 OrthoMaM phylogenetic marker: CASP3 coding sequence http://www.orthomam.[...] 2009-12-20
_[100] 간행물 Human ICE/CED-3 protease nomenclature 1996-10
_[101] 간행물 Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation 1999-04
_[102] 웹인용 Entrez Gene: CASP3 caspase 3, apoptosis-related cysteine peptidase https://www.ncbi.nlm[...]
_[103] 간행물 Construction and analysis of a modular model of caspase activation in apoptosis
_[104] 간행물 Apoptosis: an overview
_[105] 간행물 Plasticity of S2-S4 specificity pockets of executioner caspase-7 revealed by structural and kinetic analysis 2007-09
_[106] 저널 Structural and kinetic analysis of caspase-3 reveals role for s5 binding site in substrate recognition 2006-07
_[107] 저널 Caspases: structure-guided design of drugs to control cell death 2008-10
_[108] 저널 CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme 1994-12
_[109] 저널 Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase 1995-06
_[110] 저널 Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis 1995-07
_[111] 저널 Internally quenched fluorescent peptide substrates disclose the subsite preferences of human caspases 1, 3, 6, 7 and 8 2000-09
_[112] 저널 Biochemical characteristics of caspases-3, -6, -7, and -8 1997-10
_[113] 저널 Caspases: opening the boxes and interpreting the arrows 2002-01
_[114] 저널 Apoptosis and cancer: mutations within caspase genes 2009-08
_[115] 저널 Mechanisms of caspase activation 2003-12
_[116] 저널 A constitutively active and uninhibitable caspase-3 zymogen efficiently induces apoptosis 2009-12
_[117] 저널 Apoptosis: live or die--hard work either way! 2001-09
_[118] 저널 Novel procaspase-3 activating cascade mediated by lysoapoptases and its biological significances in apoptosis 2001
_[119] 저널 Zinc is a potent inhibitor of the apoptotic protease, caspase-3. A novel target for zinc in the inhibition of apoptosis 1997-07
_[120] 저널 Protective effect of mangosteen extract against beta-amyloid-induced cytotoxicity, oxidative stress and altered proteome in SK-N-SH cells http://ntur.lib.ntu.[...] 2010-05
_[121] 저널 Caspases: pharmacological manipulation of cell death 2005-10
_[122] 저널 Mitochondrial activation of apoptosis 2004-01
_[123] 저널 Caspase 3 attenuates XIAP (X-linked inhibitor of apoptosis protein)-mediated inhibition of caspase 9 2007-07
_[124] 저널 Emerging roles of caspase-3 in apoptosis 1999-02
_[125] 저널 Serum caspase-3 p17 fragment is elevated in patients with ST-segment elevation myocardial infarction: a novel observation 2011-01
_[126] 저널 Rehabilitation of a contract killer: caspase-3 directs stem cell differentiation 2008-06