Lck

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Lck
1lkkA SH2 domain.png
Dostupne strukture
PDBPretraga ortologa: PDBe 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 cMPočetak129,548,344 bp[2]
Kraj129,573,641 bp[2]
Obrazac RNK ekspresije
PBB GE LCK 204891 s at fs.png

PBB GE LCK 204890 s at fs.png
Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija transferase activity
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 protein binding
identical protein binding
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
regulation of defense response to virus 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
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
Ensembl
UniProt
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: 129.55 – 129.57 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[uredi | uredi izvor]

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[uredi | uredi izvor]

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[uredi | uredi izvor]

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[uredi | uredi izvor]

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[uredi | uredi izvor]

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[uredi | uredi izvor]

Pokazalo se da Lck interraguje sa:

Također pogledajte[uredi | uredi izvor]

Reference[uredi | uredi izvor]

  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 2021-11-29. CS1 održavanje: nepreporučeni parametar (link) CS1 održavanje: nepoznati jezik (link)
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  23. ^ a b Sade H, Krishna S, Sarin A (January 2004). "The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells". The Journal of Biological Chemistry. 279 (4): 2937–44. doi:10.1074/jbc.M309924200. PMID 14583609.
  24. ^ Prasad KV, Kapeller R, Janssen O, Repke H, Duke-Cohan JS, Cantley LC, Rudd CE (December 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 (January 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.
  26. ^ Chiang GG, Sefton BM (June 2001). "Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase". The Journal of Biological Chemistry. 276 (25): 23173–8. doi:10.1074/jbc.M101219200. PMID 11294838.
  27. ^ Lorenz U, Ravichandran KS, Pei D, Walsh CT, Burakoff SJ, Neel BG (March 1994). "Lck-dependent tyrosyl phosphorylation of the phosphotyrosine phosphatase SH-PTP1 in murine T cells". Molecular and Cellular Biology. 14 (3): 1824–34. doi:10.1128/mcb.14.3.1824. PMC 358540. PMID 8114715.
  28. ^ Koretzky GA, Kohmetscher M, Ross S (April 1993). "CD45-associated kinase activity requires lck but not T cell receptor expression in the Jurkat T cell line". The Journal of Biological Chemistry. 268 (12): 8958–64. doi:10.1016/S0021-9258(18)52965-3. PMID 8473339.
  29. ^ Ng DH, Watts JD, Aebersold R, Johnson P (January 1996). "Demonstration of a direct interaction between p56lck and the cytoplasmic domain of CD45 in vitro". The Journal of Biological Chemistry. 271 (3): 1295–300. doi:10.1074/jbc.271.3.1295. PMID 8576115.
  30. ^ Gorska MM, Stafford SJ, Cen O, Sur S, Alam R (February 2004). "Unc119, a novel activator of Lck/Fyn, is essential for T cell activation". The Journal of Experimental Medicine. 199 (3): 369–79. doi:10.1084/jem.20030589. PMC 2211793. PMID 14757743.
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  32. ^ Oda H, Kumar S, Howley PM (August 1999). "Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination". Proceedings of the National Academy of Sciences of the United States of America. 96 (17): 9557–62. Bibcode:1999PNAS...96.9557O. doi:10.1073/pnas.96.17.9557. PMC 22247. PMID 10449731.
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Dopunska literatura[uredi | uredi izvor]

Vanjski linkovi[uredi | uredi izvor]