PTPN5

PTPN5
PTPN5
Protein PTPN5 PDB 2bij.png
사용 가능한 구조
PDBOrtholog 검색: PDBe RCSB
식별자
에일리어스PTPN5, PTPSTEP, STEP, STEP, STEP61, 단백질티로신포스파타아제, 비수용체형 5, 단백질티로신포스파타아제 비수용체형 5
외부 IDOMIM : 176879 MGI : 97807 HomoloGene : 8423 GenCard : PTPN5
맞춤법
종.인간마우스
엔트레즈

84867

19259

앙상블

ENSG00000110786

ENSMUSG000030854

유니프로트

P54829

P54830

RefSeq(mRNA)

NM_001163565
NM_013643

RefSeq(단백질)

NP_001157037
NP_038671

장소(UCSC)Chr 11: 18.73 ~18.79 MbChr 7: 46.73 ~46.78 Mb
PubMed 검색[3][4]
위키데이터
인간 보기/편집마우스 표시/편집

단백질 티로신인산가수분해효소 비수용체 타입 5는 PTPN5 [5][6]유전자에 의해 인체 내에서 암호화되는 효소이다.

STEP(STrianal-Enriched 단백질 티로신 포스파타아제)라고도 알려진 비수용체 유형 5인 단백질 티로신 포스파타아제(PTP)는 [5]최초로 발견된 뇌 특이적 PTP였다.인간의 STEP 궤적은 염색체 11p15.2-p15.1에, 쥐의 STEP 유전자는 염색체 7B3-B5에 [7]매핑된다.단일 STEP 유전자는 대체적으로 결합되어 여러 개의 동질 [8][9]형태를 생성하며, 그 중 가장 잘 특징지어지는 것은 세포질46 STEP 단백질과 막 관련61 STEP [10][11]단백질이다.

기판

2015년 기준으로 ERK1/2,[12][13] p38,[12] Fyn,[14] Pyk2,[15] PTPα,[16] 글루탐산염 수용체 서브유닛 GluN2B 및 GluA2 [17][18][19]등 7가지 알려진 STEP 대상물이 확인되었다.키나아제(ERK1/2, p38, Fyn 및 Pyk2)의 STEP 탈인산화효소는 키나아제 활성화 루프 내의 조절 티로신에서 일어나 비활성화된다.PTPα에 대한 조절 티로신의 탈인화는 PTPα가 세포질에서 지질 뗏목으로 전이되는 것을 방지하며, 여기서 [16]Fyn은 정상적으로 활성화된다.따라서 STEP는 Fyn을 직접 비활성화하며 또한 Fyn을 활성화하는 구획으로의 PTPα 전이를 방지한다.GluN2B 및 GluA2의 STEP 탈인화는 NMDAR(GluN1/GluN2B) 및 AMPAR(GluA1/GluA2)의 내부화로 이어진다.따라서 STEP의 한 가지 기능은 키나아제 불활성화와 시냅스 강화 발달에 중요한 수용체 내부화를 통해 시냅스 강화에 반대하는 것이다.

임상적 의의

STEP 레벨은 몇 가지 질병으로 중단됩니다.알츠하이머병(AD)은 인간 피질과 AD의 [17][20][19][21]여러 마우스 모델 모두에서 STEP 발현 증가와 관련된 첫 번째 질병이었다.STEP은 [22]연약한 X증후군,[23] 정신분열증,[24] 파킨슨병에서도 증가한다.AD 및 FXS 마우스 모델에서 STEP 표현의 유전적 감소는 많은 인지적 및 행동적 결함을 [22][19]되돌린다.이제 다른 연구실에서도 몇 가지 추가 장애에서 STEP 활성도가 감소하는 것으로 나타났습니다.따라서 헌팅턴병,[25][26] 뇌허혈,[27] 알코올 남용,[28][29][30] 스트레스 장애에서 [31][32]STEP 수준이나 활동이 감소합니다.이 새로운 모델은 시냅스 사이트에서 최적의 STEP 레벨이 필요하며, 높은 레벨과 낮은 레벨 모두 시냅스 [33][34]기능을 방해함을 시사한다.

억제

현재 몇 가지 STEP 억제제가 발견되었습니다.[15][35]GlaxoSmithKline은 2014년 DPAc(Discovery Partnerships with Academy)의 새로운 프로젝트로 STEP을 선택했습니다.이는 약물 발견에 있어 비교적 새로운 프로그램이며, GSK의 약물 발견 전문지식을 학계와 결합하여 검증된 대상의 새로운 억제제를 발견한다.

레퍼런스

  1. ^ a b c GRCh38: 앙상블 릴리즈 89: ENSG00000110786 - 앙상블, 2017년 5월
  2. ^ a b c GRCm38: 앙상블 릴리즈 89: ENSMUSG000030854 - 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.
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  6. ^ "Entrez Gene: PTPN5 protein tyrosine phosphatase, non-receptor type 5 (striatum-enriched)".
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  8. ^ Sharma E, Zhao F, Bult A, Lombroso PJ (Aug 1995). "Identification of two alternatively spliced transcripts of STEP: a subfamily of brain-enriched protein tyrosine phosphatases". Brain Research. Molecular Brain Research. 32 (1): 87–93. doi:10.1016/0169-328x(95)00066-2. PMID 7494467.
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  16. ^ a b Xu J, Kurup P, Foscue E, Lombroso PJ (May 2015). "STriatal-Enriched protein tyrosine Phosphatase (STEP) Regulates the PTPα/Fyn Signaling Pathway". Journal of Neurochemistry. 134 (4): 629–41. doi:10.1111/jnc.13160. PMC 4516628. PMID 25951993.
  17. ^ a b Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P (Aug 2005). "Regulation of NMDA receptor trafficking by amyloid-beta". Nature Neuroscience. 8 (8): 1051–8. doi:10.1038/nn1503. PMID 16025111. S2CID 25182223.
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  19. ^ a b c Zhang Y, Kurup P, Xu J, Carty N, Fernandez SM, Nygaard HB, Pittenger C, Greengard P, Strittmatter SM, Nairn AC, Lombroso PJ (Nov 2010). "Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model". Proceedings of the National Academy of Sciences of the United States of America. 107 (44): 19014–9. Bibcode:2010PNAS..10719014Z. doi:10.1073/pnas.1013543107. PMC 2973892. PMID 20956308.
  20. ^ Kurup P, Zhang Y, Xu J, Venkitaramani DV, Haroutunian V, Greengard P, Nairn AC, Lombroso PJ (Apr 2010). "Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61". The Journal of Neuroscience. 30 (17): 5948–57. doi:10.1523/JNEUROSCI.0157-10.2010. PMC 2868326. PMID 20427654.
  21. ^ Zhang Y, Kurup P, Xu J, Anderson GM, Greengard P, Nairn AC, Lombroso PJ (Nov 2011). "Reduced levels of the tyrosine phosphatase STEP block β amyloid-mediated GluA1/GluA2 receptor internalization". Journal of Neurochemistry. 119 (3): 664–72. doi:10.1111/j.1471-4159.2011.07450.x. PMC 3192910. PMID 21883219.
  22. ^ a b Goebel-Goody SM, Wilson-Wallis ED, Royston S, Tagliatela SM, Naegele JR, Lombroso PJ (Jul 2012). "Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model". Genes, Brain, and Behavior. 11 (5): 586–600. doi:10.1111/j.1601-183X.2012.00781.x. PMC 3922131. PMID 22405502.
  23. ^ Carty NC, Xu J, Kurup P, Brouillette J, Goebel-Goody SM, Austin DR, Yuan P, Chen G, Correa PR, Haroutunian V, Pittenger C, Lombroso PJ (2012). "The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications". Translational Psychiatry. 2 (7): e137. doi:10.1038/tp.2012.63. PMC 3410627. PMID 22781170.
  24. ^ Kurup PK, Xu J, Videira RA, Ononenyi C, Baltazar G, Lombroso PJ, Nairn AC (Jan 2015). "STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson's disease". Proceedings of the National Academy of Sciences of the United States of America. 112 (4): 1202–7. Bibcode:2015PNAS..112.1202K. doi:10.1073/pnas.1417423112. PMC 4313846. PMID 25583483.
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  36. ^ Baguley TD, Nairn AC, Lombroso PJ, Ellman JA (March 2015). "Synthesis of benzopentathiepin analogs and their evaluation as inhibitors of the phosphatase STEP". Bioorg. Med. Chem. Lett. 25 (5): 1044–6. doi:10.1016/j.bmcl.2015.01.020. PMC 4334692. PMID 25666825.

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