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Lck

S Wikipedije, slobodne enciklopedije
Lck
Dostupne strukture
PDBPretraga ortologa: E9PI33 PDBe E9PI33 RCSB
Spisak PDB ID kodova

1BHF, 1BHH, 1CWD, 1CWE, 1FBZ, 1H92, 1IJR, 1KIK, 1LCJ, 1LCK, 1LKK, 1LKL, 1Q68, 1Q69, 1QPC, 1QPD, 1QPE, 1QPJ, 1X27, 2IIM, 2OF2, 2OF4, 2OFU, 2OFV, 2OG8, 2PL0, 2ZM1, 2ZM4, 2ZYB, 3AC1, 3AC2, 3AC3, 3AC4, 3AC5, 3AC8, 3ACJ, 3ACK, 3AD4, 3AD5, 3AD6, 3B2W, 3BRH, 3BYM, 3BYO, 3BYS, 3BYU, 3KMM, 3KXZ, 3LCK, 3MPM, 4D8K, 4C3F

Identifikatori
AliasiLCK
Vanjski ID-jeviOMIM: 153390 MGI: 96756 HomoloGene: 3911 GeneCards: LCK
Lokacija gena (čovjek)
Hromosom 1 (čovjek)
Hrom.Hromosom 1 (čovjek)[1]
Hromosom 1 (čovjek)
Genomska lokacija za Lck
Genomska lokacija za Lck
Bend1p35.2Početak32,251,239 bp[1]
Kraj32,286,165 bp[1]
Lokacija gena (miš)
Hromosom 4 (miš)
Hrom.Hromosom 4 (miš)[2]
Hromosom 4 (miš)
Genomska lokacija za Lck
Genomska lokacija za Lck
Bend4 D2.2|4 63.26 cMPočetak129,442,137 bp[2]
Kraj129,467,434 bp[2]
Obrazac RNK ekspresije


Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija• aktivnost sa transferazom
• nucleotide binding
• protein kinase activity
• CD4 receptor binding
• ATPase binding
• SH2 domain binding
• CD8 receptor binding
• phosphatidylinositol 3-kinase binding
• protein C-terminus binding
• GO:0001948, GO:0016582 vezivanje za proteine
• vezivanje identičnih proteina
• protein phosphatase binding
• ATP binding
• protein kinase binding
• phosphatidylinositol-4,5-bisphosphate 3-kinase activity
• kinase activity
• protein serine/threonine phosphatase activity
• non-membrane spanning protein tyrosine kinase activity
• phosphotyrosine residue binding
• protein tyrosine kinase activity
• T cell receptor binding
• signaling receptor binding
Ćelijska komponenta• citoplazma
• citosol
• membrana
• extrinsic component of cytoplasmic side of plasma membrane
• immunological synapse
• Egzosom
• pericentriolar material
• Lipidni splav
• ćelijska membrana
Biološki proces• B cell receptor signaling pathway
• release of sequestered calcium ion into cytosol
• Hematopoeza
• Fosforilacija
• transmembrane receptor protein tyrosine kinase signaling pathway
• positive regulation of T cell receptor signaling pathway
• T cell costimulation
• GO:0019049, GO:0030683 mitigation of host defenses by virus
• platelet activation
• T cell differentiation
• regulation of cell population proliferation
• cellular zinc ion homeostasis
• regulation of lymphocyte activation
• peptidyl-tyrosine autophosphorylation
• T cell receptor signaling pathway
• positive regulation of intrinsic apoptotic signaling pathway
• leukocyte migration
• positive regulation of T cell activation
• GO:0016576 protein dephosphorylation
• Urođeni imunski sistem
• phosphatidylinositol phosphate biosynthetic process
• GO:0022415 viral process
• protein phosphorylation
• activation of cysteine-type endopeptidase activity involved in apoptotic process
• Ćelijska migracija
• peptidyl-tyrosine phosphorylation
• interleukin-7-mediated signaling pathway
• positive regulation of protein kinase B signaling
• Ćelijska diferencijacija
• positive regulation of heterotypic cell-cell adhesion
• positive regulation of leukocyte cell-cell adhesion
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

3932

16818

Ensembl

ENSG00000182866

ENSMUSG00000000409

UniProt

P06239

P06240

RefSeq (mRNK)

NM_001042771
NM_005356
NM_001330468

NM_001162432
NM_001162433
NM_010693

RefSeq (bjelančevina)

NP_001036236
NP_001317397
NP_005347

NP_001155904
NP_001155905
NP_034823

Lokacija (UCSC)Chr 1: 32.25 – 32.29 MbChr 4: 129.44 – 129.47 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Lck ili limfocitno-specifična protein tirozin-kinaza jest 56-kDa enzim koji je kod ljudi kodiran genom sa hromosoma 1. Ovaj protein nalazi se unutar specijalizoiranih ćelija imunskog sistema zvanih limfociti. Lck je tirozin-kinaza, koja fosforilizira tirozinske ostatke određenih proteina uključenih u unutarćelijske signalne puteve ovih limfocita. Član je Src porodice tirozin-kinaza.

Funkcija Lck je proučavana korištenjem nekoliko biokemijskih metoda, uključujući genski nokaut (nokaut-miševe), Jurkat-ćelije deficitarne Lck (JCaM1.6) i siRNK posredovane interferencije RNK.

Aminokiselinska sekvenca

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Dužina polipeptidnog lanca je 509 aminokiselina, a molekulska težina 58.001 Da.[5]

1020304050
MGCGCSSHPEDDWMENIDVCENCHYPIVPLDGKGTLLIRNGSEVRDPLVT
YEGSNPPASPLQDNLVIALHSYEPSHDGDLGFEKGEQLRILEQSGEWWKA
QSLTTGQEGFIPFNFVAKANSLEPEPWFFKNLSRKDAERQLLAPGNTHGS
FLIRESESTAGSFSLSVRDFDQNQGEVVKHYKIRNLDNGGFYISPRITFP
GLHELVRHYTNASDGLCTRLSRPCQTQKPQKPWWEDEWEVPRETLKLVER
LGAGQFGEVWMGYYNGHTKVAVKSLKQGSMSPDAFLAEANLMKQLQHQRL
VRLYAVVTQEPIYIITEYMENGSLVDFLKTPSGIKLTINKLLDMAAQIAE
GMAFIEERNYIHRDLRAANILVSDTLSCKIADFGLARLIEDNEYTAREGA
KFPIKWTAPEAINYGTFTIKSDVWSFGILLTEIVTHGRIPYPGMTNPEVI
QNLERGYRMVRPDNCPEELYQLMRLCWKERPEDRPTFDYLRSVLEDFFTA
TEGQYQPQP

Struktura

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Lck je 56-kD-ski protein. N-terminalni rep Lck je miristoiliran i palmitoiliran, koji vezuje protein za ćelijsku plazmamembranu. Protein dalje sadrži SH3-domen, SH2-domen i u C-terminalnom dijelu domen tirozin-kinaza. Dva glavna mjesta fosforilacije na Lck su tirozini 394 i 505. Prvo je autofosforilaciono mjesto i povezano je sa aktivacijom proteina. Potonje je fosforilirano pomoću Csk, koja inhibira Lck jer se protein savija i vezuje za sopstveni SH2-domen. Lck stoga služi kao poučan primjer da fosforilacija proteina može rezultirati i aktivacijom i inhibicijom.

T-ćelijska signalizacija

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Lck se najčešće nalazi u T-ćelijaama. Povezuje se sa citoplazmatskim repovima CD4 i CD8 koreceptora na T-pomoćnim ćelijama i citotoksičnim T-ćelijama,[6][7] za pomoć pri prenosu signala iz kompleksa T-ćelijskih receptora (TCR). Kada je T-ćelijski receptor zahvaćen specifičnim antigenom predstavljenim MHC, Lck djeluje da fosforilira unutarćelijske lance CD3 i CD3-zeta (ζ-lanci) TCR kompleksa, omogućavajući još jednu citoplazmatsku tirozin-kinazu, zvanu ZAP-70, da se veže za njih. Lck zatim fosforilira i aktivira ZAP-70, koji zauzvrat fosforilira drugu molekulu u signalnoj kaskadi zvanoj LAT (skraćeno od Linker za aktivaciju T-ćelija), transmembranski protein koji služi kao mjesto vezanja brojnih drugih proteina, od kojih su najvažniji Shc-Grb2-SOS, PI3K i fosfolipaza C ( PLC). Dodatno, nakon aktivacije T-ćelija, dio aktivnog Lck kinaze, translocira se izvan lipidnog splava (LR) u unutrašnjih lipidnih splavova, gdje stupa u interakciju sa i aktivira LR-rezidentni Fyn, koji uključen je u dalju aktivaciju nizvodne signalizacije.[8][9]

Fosforilacija tirozinske kaskade koju su pokrenuli Lck i Fyn kulminira unutarćelijskom mobilizacijom kalcijevih (Ca2+) iona i aktivacijom važne signalizacije kaskade unutar limfocita. To uključuje Ras-MEK-ERK puta, koji dalje aktivira određene transkripcijski faktor, kao što su NFAT, NF-κB i AP-1. Ovi faktori transkripcije regulišu proizvodnju pletora genskih proizvoda, najistaknutijih, citokina, kao što je interleukin-2 koji promoviraju dugotrajnu proliferaciju i diferencijaciju aktiviranih limfocita. Pored značaja Lck i Fyn u signalizaciji receptora T-ćelija, pokazalo se da su ove dvije src kinaze važne u TLR-posredovanoj signalizaciji u T-ćelijama.[10]

Podloge

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Lck tirozin fosforilira brojne proteine, od kojih su najvažniji CD3-receptor, CEACAM1, ZAP-70, SLP-76, IL-2 receptor, Protein kinaza C, ITK, PLC, Src dvodomenska homologija (SHC), RasGAP , Cbl, Vav1 i PI3K.

Inhibicija

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U T-ćelijama u mirovanju, Lck je konstitutivno inhibiran fosforilacijom Csk na tirozinu 505. Lck je također inhibiran defosforilacijom SHP-1 na tirozinu 394. Lck također može biti inhibiran pomoću Cbl ubikvitin-ligaze, koja je dio ubikvitinom-posredovanog puta.[11]

Saraktinib, specifični inhibitor LCK, narušava održavanje ljudskih T-ALL ćelija in vitro kao i in vivo ciljajući ovu tirozin-kinazu u ćelije koje pokazuju visok nivo lipidnih splavova.[12]

Masitinib također inhibira Lck, što može imati određeni uticaj na njegove terapeutske efekte kod mastocitoma.[13]

Opisano je da inhibitor HSP90 NVP-BEP800 utiče na stabilnost LCK kinaze i rast T-ćelija akutne limfoblastne leukemije.[14]

Interakcije

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Pokazalo se da Lck interraguje sa:

Također pogledajte

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Reference

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000182866 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000409 - Ensembl, maj 2017
  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.
  5. ^ "UniProt, P06239" (jezik: eng.). Pristupljeno 29. 11. 2021.CS1 održavanje: nepoznati jezik (link)
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  7. ^ Barber EK, Dasgupta JD, Schlossman SF, Trevillyan JM, Rudd CE (maj 1989). "The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex". Proceedings of the National Academy of Sciences of the United States of America. 86 (9): 3277–81. Bibcode:1989PNAS...86.3277B. doi:10.1073/pnas.86.9.3277. PMC 287114. PMID 2470098.
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  22. ^ Hanada T, Lin L, Chandy KG, Oh SS, Chishti AH (oktobar 1997). "Human homologue of the Drosophila discs large tumor suppressor binds to p56lck tyrosine kinase and Shaker type Kv1.3 potassium channel in T lymphocytes". The Journal of Biological Chemistry. 272 (43): 26899–904. doi:10.1074/jbc.272.43.26899. PMID 9341123.
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  24. ^ Prasad KV, Kapeller R, Janssen O, Repke H, Duke-Cohan JS, Cantley LC, Rudd CE (decembar 1993). "Phosphatidylinositol (PI) 3-kinase and PI 4-kinase binding to the CD4-p56lck complex: the p56lck SH3 domain binds to PI 3-kinase but not PI 4-kinase". Molecular and Cellular Biology. 13 (12): 7708–17. doi:10.1128/mcb.13.12.7708. PMC 364842. PMID 8246987.
  25. ^ Yu CL, Jin YJ, Burakoff SJ (januar 2000). "Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation". The Journal of Biological Chemistry. 275 (1): 599–604. doi:10.1074/jbc.275.1.599. PMID 10617656.
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  31. ^ a b Thome M, Duplay P, Guttinger M, Acuto O (juni 1995). "Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complex". The Journal of Experimental Medicine. 181 (6): 1997–2006. doi:10.1084/jem.181.6.1997. PMC 2192070. PMID 7539035.
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Dopunska literatura

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Vanjski linkovi

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