ERN1

ERN1
사용 가능한 구조
PDB	Ortholog 검색: PDBe RCSB
PDB ID 코드 목록
	2Hz6, 3P23, 4U6R, 4Z7G, 4Z7H, 4YZC, 4YZ9, 4YZD, 5HGI
식별자
에일리어스	ERN1, IRE1, IRE1P, IRE1a, hIRE1p, 핵 시그널링 1로의 소포체
외부 ID	OMIM: 604033 MGI: 1930134 HomoloGene: 55580 GenCard: ERN1
유전자 위치(인간)
크르.	17번 염색체(인간)
끝.	64,130,819 bp
유전자 위치(마우스)
크르.	11번 염색체(쥐)
끝.	106,378,678 bp
RNA발현패턴
	상단 표시 위치:
	이하선; ; 양수; ; 이차 난모세포; ; 정낭포; ; 췌장체; ; 부고환 카푸트; ; 생식 상피; ; 자궁경관; ; 내피 세포; ; 피;
	추가 참조 표현식 데이터
	추가 참조 표현식 데이터
유전자 존재론
분자 함수	금속 이온 결합; 뉴클레오티드 결합; ADP 바인딩; 리보핵산가수분해효소활성; 동일단백질결합; 단백질인산화효소활성; 트랜스페라아제 활성; 마그네슘 이온 결합; 가수분해효소활성; Hsp70 단백질 결합; 키나아제활성; Hsp90 단백질 결합; 촉매 활성; 엔도핵산가수분해효소활성; ATP 결합; 효소결합; GO:0001948 단백질 결합; 엔도리보핵산가수분해효소활성; 단백질세린/트레오닌인산화효소활성; 혈소판유래성장인자수용체결합; 단백질 호모다이머화; 전개단백질결합;
셀룰러 컴포넌트	AIP1-IRE1 복합체; 세포질; 막의 적분 성분; 미토콘드리아; IRE1-TRAF2-ASK1 복합체; IRE1-RACK1-PP2A 복합체; 핵내막; Ire1 복합체; 막; 소포체막의 일체 성분; 소포체; 소포체막;
생물학적 과정	소포체 전개단백질반응의 조절; mRNA 이화 과정; 전사, DNA 템플릿; 인슐린 대사 과정; 펩티딜세린자동인산화; 혈관내피성장인자 자극에 대한 세포반응; 단백질 자기인산화; 대사; 아포토시스 과정; mRNA 스플라이싱, 내핵분열 및 결찰을 통한; 소포체 응력에 대한 내인성 아포토시스 시그널링; 포도당 자극에 대한 세포 반응; 펩티딜세린트랜스오토인산화; 단백질인산화; 전개 단백질에 대한 반응; mRNA 처리; 소포체 응력에 대한 반응; 전사조절, DNA템플릿화; 내피세포증식; 거시 자동 식도 조절; 인산화; 소포체전개단백질반응; 혈관관련 평활근세포증식의 양성조절; RNA포스포디에스테르결합가수분해,내핵분해; RNA 스플라이싱의 양성 조절; IRE1 매개 전개단백질반응; mRNA 처리에 관여하는 mRNA 절단; mRNA 절단; 전개 단백질에 대한 세포 반응;
	출처:아미고 / QuickGO
맞춤법
	2081
	78943
	ENSG00000178607
	ENSMUSG000020715
	O75460
	Q9EQY0
	NM_152461; NM_001433
	NM_023913
	NP_001424
	NP_076402
	위키데이터
인간 보기/편집	마우스 표시/편집

세린/트레오닌-단백질인산화효소/엔도리보핵산가수분해효소 이노시톨 요구효소 1α(IRE1α)는 사람에서 ERN1 ^[5]^[6]유전자에 의해 암호화되는 효소이다.

기능.

이 유전자에 의해 코드된 단백질은 효모 Ire1 유전자 생성물의 인간 상동체인 1단백질 신호를 보내는 ER이다.이 단백질은 내인산화효소 활성과 엔도리보핵산가수분해효소 활성을 가지며, 내소체 기반 스트레스 신호(주로 전개된 단백질 반응)에 대한 반응으로서 유전자 발현을 변화시키는 데 중요하다.이 ^[6]유전자에 대해 다른 아이소폼을 코드하는 2개의 대체 스플라이스 전사 변형이 발견되었다.

시그널링

IRE1α는 엔도핵산가수분해효소 및 트랜스-자동인산화인산화효소 도메인의 두 가지 기능성 효소 도메인을 가지고 있다.활성화해서, IRE1α과 틀에 얽매이지 않는 RNAsplicing 활동을 수행할 때, X박스 결합 단백질 1(XBP1)mRNA에서, 그리고 그것은 기능적 전사 인자, XBP1s로 번역한 인트론을 제거하는 oligomerizes.[7]XBP1s 응급실 chaperones과 소포체로는 facilita 저하(ERAD)유전자 관련된 upregulates.ER 스트레스로부터의 회복.

상호 작용

ERN1은 열충격 단백질 90kDa 알파(세포산) 멤버 A1과 ^[8]상호작용하는 것으로 나타났다.

억제제

RNase 도메인의 촉매 코어 또는 키나아제 도메인의 ATP 결합 포켓을 대상으로 하는 두 가지 유형의 억제제가 존재한다.

RNase 도메인 억제제

살리실알데히드(3-메톡시-6-브로모살리실알데히드,^[9] 4μ8C,^[10] MKC-3946,^[11] STF-083010,^[12] 토요카마이신).^[13]

ATP결합포켓

수니티닙과 APY29는 ATP 결합 포켓을 억제하지만 IRE1α RNase 도메인을 알로스테릭하게 활성화한다.

화합물 3은 키나아제 활성, 올리고머화 및 RNase ^[14]활성을 방지한다.

레퍼런스

^ ^a ^b ^c GRCh38: 앙상블 릴리즈 89: ENSG00000178607 - 앙상블, 2017년 5월
^ ^a ^b ^c GRCm38: 앙상블 릴리즈 89: ENSMUSG000020715 - 앙상블, 2017년 5월
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Tirasophon W, Welihinda AA, Kaufman RJ (Jul 1998). "A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells". Genes Dev. 12 (12): 1812–24. doi:10.1101/gad.12.12.1812. PMC 316900. PMID 9637683.
^ ^a ^b "Entrez Gene: ERN1 endoplasmic reticulum to nucleus signalling 1".
^ Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D (January 2002). "IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA". Nature. 415 (6867): 92–6. doi:10.1038/415092a. PMID 11780124. S2CID 4319118.
^ Marcu MG, Doyle M, Bertolotti A, Ron D, Hendershot L, Neckers L (December 2002). "Heat shock protein 90 modulates the unfolded protein response by stabilizing IRE1alpha". Mol. Cell. Biol. 22 (24): 8506–13. doi:10.1128/MCB.22.24.8506-8513.2002. PMC 139892. PMID 12446770.
^ Volkmann K, Lucas JL, Vuga D, Wang X, Brumm D, Stiles C, Kriebel D, Der-Sarkissian A, Krishnan K, Schweitzer C, Liu Z, Malyankar UM, Chiovitti D, Canny M, Durocher D, Sicheri F, Patterson JB (April 2011). "Potent and selective inhibitors of the inositol-requiring enzyme 1 endoribonuclease". J. Biol. Chem. 286 (14): 12743–55. doi:10.1074/jbc.M110.199737. PMC 3069474. PMID 21303903.
^ Cross BC, Bond PJ, Sadowski PG, Jha BK, Zak J, Goodman JM, Silverman RH, Neubert TA, Baxendale IR, Ron D, Harding HP (April 2012). "The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule". Proc. Natl. Acad. Sci. U.S.A. 109 (15): E869–78. doi:10.1073/pnas.1115623109. PMC 3326519. PMID 22315414.
^ Mimura N, Fulciniti M, Gorgun G, Tai YT, Cirstea D, Santo L, Hu Y, Fabre C, Minami J, Ohguchi H, Kiziltepe T, Ikeda H, Kawano Y, French M, Blumenthal M, Tam V, Kertesz NL, Malyankar UM, Hokenson M, Pham T, Zeng Q, Patterson JB, Richardson PG, Munshi NC, Anderson KC (June 2012). "Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma". Blood. 119 (24): 5772–81. doi:10.1182/blood-2011-07-366633. PMC 3382937. PMID 22538852.
^ Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, Solow-Cordero DE, Bouley DM, Offner F, Niwa M, Koong AC (January 2011). "Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma". Blood. 117 (4): 1311–4. doi:10.1182/blood-2010-08-303099. PMC 3056474. PMID 21081713.
^ Ri M, Tashiro E, Oikawa D, Shinjo S, Tokuda M, Yokouchi Y, Narita T, Masaki A, Ito A, Ding J, Kusumoto S, Ishida T, Komatsu H, Shiotsu Y, Ueda R, Iwawaki T, Imoto M, Iida S (July 2012). "Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing". Blood Cancer J. 2 (7): e79. doi:10.1038/bcj.2012.26. PMC 3408640. PMID 22852048.
^ Wang L, Perera BG, Hari SB, Bhhatarai B, Backes BJ, Seeliger MA, Schürer SC, Oakes SA, Papa FR, Maly DJ (December 2012). "Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors". Nat. Chem. Biol. 8 (12): 982–9. doi:10.1038/nchembio.1094. PMC 3508346. PMID 23086298.

추가 정보

Katayama T, Imaizumi K, Sato N, et al. (2000). "Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response". Nat. Cell Biol. 1 (8): 479–85. doi:10.1038/70265. PMID 10587643. S2CID 30259483.
Urano F, Wang X, Bertolotti A, et al. (2000). "Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1". Science. 287 (5453): 664–6. doi:10.1126/science.287.5453.664. PMID 10650002. S2CID 9154084.
Dias Neto E, Correa RG, Verjovski-Almeida S, et al. (2000). "Shotgun sequencing of the human transcriptome with ORF expressed sequence tags". Proc. Natl. Acad. Sci. U.S.A. 97 (7): 3491–6. doi:10.1073/pnas.97.7.3491. PMC 16267. PMID 10737800.
Iwawaki T, Hosoda A, Okuda T, et al. (2001). "Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress". Nat. Cell Biol. 3 (2): 158–64. doi:10.1038/35055065. PMID 11175748. S2CID 7756732.
Yoneda T, Imaizumi K, Oono K, et al. (2001). "Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress". J. Biol. Chem. 276 (17): 13935–40. doi:10.1074/jbc.M010677200. PMID 11278723.
Lee K, Tirasophon W, Shen X, et al. (2002). "IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response". Genes Dev. 16 (4): 452–66. doi:10.1101/gad.964702. PMC 155339. PMID 11850408.
Liu CY, Wong HN, Schauerte JA, Kaufman RJ (2002). "The protein kinase/endoribonuclease IRE1alpha that signals the unfolded protein response has a luminal N-terminal ligand-independent dimerization domain". J. Biol. Chem. 277 (21): 18346–56. doi:10.1074/jbc.M112454200. PMID 11897784.
Nishitoh H, Matsuzawa A, Tobiume K, et al. (2002). "ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats". Genes Dev. 16 (11): 1345–55. doi:10.1101/gad.992302. PMC 186318. PMID 12050113.
Marcu MG, Doyle M, Bertolotti A, et al. (2003). "Heat Shock Protein 90 Modulates the Unfolded Protein Response by Stabilizing IRE1α". Mol. Cell. Biol. 22 (24): 8506–13. doi:10.1128/MCB.22.24.8506-8513.2002. PMC 139892. PMID 12446770.
Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
Liu CY, Xu Z, Kaufman RJ (2003). "Structure and intermolecular interactions of the luminal dimerization domain of human IRE1alpha". J. Biol. Chem. 278 (20): 17680–7. doi:10.1074/jbc.M300418200. PMID 12637535.
Kaneko M, Niinuma Y, Nomura Y (2004). "Activation signal of nuclear factor-kappa B in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2". Biol. Pharm. Bull. 26 (7): 931–5. doi:10.1248/bpb.26.931. PMID 12843613.
Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
Shang J, Lehrman MA (2004). "Discordance of UPR signaling by ATF6 and Ire1p-XBP1 with levels of target transcripts". Biochem. Biophys. Res. Commun. 317 (2): 390–6. doi:10.1016/j.bbrc.2004.03.058. PMID 15063770.
Oono K, Yoneda T, Manabe T, et al. (2004). "JAB1 participates in unfolded protein responses by association and dissociation with IRE1". Neurochem. Int. 45 (5): 765–72. doi:10.1016/j.neuint.2004.01.003. PMID 15234121. S2CID 11627892.
Huang ZM, Tan T, Yoshida H, et al. (2005). "Activation of Hepatitis B Virus S Promoter by a Cell Type-Restricted IRE1-Dependent Pathway Induced by Endoplasmic Reticulum Stress". Mol. Cell. Biol. 25 (17): 7522–33. doi:10.1128/MCB.25.17.7522-7533.2005. PMC 1190304. PMID 16107700.
Kimura K, Wakamatsu A, Suzuki Y, et al. (2006). "Diversification of transcriptional modulation: Large-scale identification and characterization of putative alternative promoters of human genes". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
Hetz C, Bernasconi P, Fisher J, et al. (2006). "Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha". Science. 312 (5773): 572–6. doi:10.1126/science.1123480. PMID 16645094. S2CID 9135901.
Oikawa D, Tokuda M, Iwawaki T (2007). "Site-specific cleavage of CD59 mRNA by endoplasmic reticulum-localized ribonuclease, IRE1". Biochem. Biophys. Res. Commun. 360 (1): 122–7. doi:10.1016/j.bbrc.2007.06.020. PMID 17585877.

[refGRCh38Ensembl-1] GRCh38: 앙상블 릴리즈 89: ENSG00000178607 - 앙상블, 2017년 5월

[refGRCm38Ensembl-2] GRCm38: 앙상블 릴리즈 89: ENSMUSG000020715 - 앙상블, 2017년 5월

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid9637683-5] Tirasophon W, Welihinda AA, Kaufman RJ (Jul 1998). "A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells". Genes Dev. 12 (12): 1812–24. doi:10.1101/gad.12.12.1812. PMC 316900. PMID 9637683.

[entrez-6] "Entrez Gene: ERN1 endoplasmic reticulum to nucleus signalling 1".

[pmid11780124-7] Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D (January 2002). "IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA". Nature. 415 (6867): 92–6. doi:10.1038/415092a. PMID 11780124. S2CID 4319118.

[pmid12446770-8] Marcu MG, Doyle M, Bertolotti A, Ron D, Hendershot L, Neckers L (December 2002). "Heat shock protein 90 modulates the unfolded protein response by stabilizing IRE1alpha". Mol. Cell. Biol. 22 (24): 8506–13. doi:10.1128/MCB.22.24.8506-8513.2002. PMC 139892. PMID 12446770.

[pmid21303903-9] Volkmann K, Lucas JL, Vuga D, Wang X, Brumm D, Stiles C, Kriebel D, Der-Sarkissian A, Krishnan K, Schweitzer C, Liu Z, Malyankar UM, Chiovitti D, Canny M, Durocher D, Sicheri F, Patterson JB (April 2011). "Potent and selective inhibitors of the inositol-requiring enzyme 1 endoribonuclease". J. Biol. Chem. 286 (14): 12743–55. doi:10.1074/jbc.M110.199737. PMC 3069474. PMID 21303903.

[pmid22315414-10] Cross BC, Bond PJ, Sadowski PG, Jha BK, Zak J, Goodman JM, Silverman RH, Neubert TA, Baxendale IR, Ron D, Harding HP (April 2012). "The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule". Proc. Natl. Acad. Sci. U.S.A. 109 (15): E869–78. doi:10.1073/pnas.1115623109. PMC 3326519. PMID 22315414.

[pmid22538852-11] Mimura N, Fulciniti M, Gorgun G, Tai YT, Cirstea D, Santo L, Hu Y, Fabre C, Minami J, Ohguchi H, Kiziltepe T, Ikeda H, Kawano Y, French M, Blumenthal M, Tam V, Kertesz NL, Malyankar UM, Hokenson M, Pham T, Zeng Q, Patterson JB, Richardson PG, Munshi NC, Anderson KC (June 2012). "Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma". Blood. 119 (24): 5772–81. doi:10.1182/blood-2011-07-366633. PMC 3382937. PMID 22538852.

[pmid21081713-12] Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, Solow-Cordero DE, Bouley DM, Offner F, Niwa M, Koong AC (January 2011). "Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma". Blood. 117 (4): 1311–4. doi:10.1182/blood-2010-08-303099. PMC 3056474. PMID 21081713.

[pmid22852048-13] Ri M, Tashiro E, Oikawa D, Shinjo S, Tokuda M, Yokouchi Y, Narita T, Masaki A, Ito A, Ding J, Kusumoto S, Ishida T, Komatsu H, Shiotsu Y, Ueda R, Iwawaki T, Imoto M, Iida S (July 2012). "Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing". Blood Cancer J. 2 (7): e79. doi:10.1038/bcj.2012.26. PMC 3408640. PMID 22852048.

[pmid23086298-14] Wang L, Perera BG, Hari SB, Bhhatarai B, Backes BJ, Seeliger MA, Schürer SC, Oakes SA, Papa FR, Maly DJ (December 2012). "Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors". Nat. Chem. Biol. 8 (12): 982–9. doi:10.1038/nchembio.1094. PMC 3508346. PMID 23086298.

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