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Q95KR7

- LCK_SAISC

UniProt

Q95KR7 - LCK_SAISC

Protein

Proto-oncogene tyrosine-protein kinase LCK

Gene

LCK

Organism
Saimiri sciureus (Common squirrel monkey)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 91 (01 Oct 2014)
      Sequence version 3 (23 Jan 2007)
      Previous versions | rss
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    Functioni

    Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosines residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP By similarity.By similarity

    Catalytic activityi

    ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation

    Enzyme regulationi

    The relative activities of the inhibitory tyrosine-protein kinase CSK and the activating tyrosine-protein phosphatase PTPRC/CD45 determine the level of LCK activity. These interactions allow rapid and efficient activation of LCK in response to TCR stimulation By similarity.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei273 – 2731ATPPROSITE-ProRule annotation
    Active sitei364 – 3641Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi251 – 2599ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. non-membrane spanning protein tyrosine kinase activity Source: UniProtKB-EC
    3. protein serine/threonine phosphatase activity Source: UniProtKB
    4. protein tyrosine kinase activity Source: UniProtKB
    5. SH2 domain binding Source: UniProtKB

    GO - Biological processi

    1. activation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
    2. cellular zinc ion homeostasis Source: UniProtKB
    3. dephosphorylation Source: GOC
    4. peptidyl-tyrosine phosphorylation Source: GOC
    5. positive regulation of intrinsic apoptotic signaling pathway Source: UniProtKB
    6. positive regulation of T cell activation Source: UniProtKB
    7. response to drug Source: UniProtKB
    8. T cell differentiation Source: UniProtKB

    Keywords - Molecular functioni

    Kinase, Transferase, Tyrosine-protein kinase

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Proto-oncogene tyrosine-protein kinase LCK (EC:2.7.10.2)
    Alternative name(s):
    Lymphocyte cell-specific protein-tyrosine kinase
    p56-LCK
    Gene namesi
    Name:LCK
    OrganismiSaimiri sciureus (Common squirrel monkey)
    Taxonomic identifieri9521 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniPlatyrrhiniCebidaeSaimiriinaeSaimiri

    Subcellular locationi

    Cytoplasm By similarity. Cell membrane By similarity; Lipid-anchor By similarity; Cytoplasmic side By similarity
    Note: Present in lipid rafts in an inactive form.By similarity

    GO - Cellular componenti

    1. membrane raft Source: UniProtKB
    2. pericentriolar material Source: UniProtKB
    3. plasma membrane Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Membrane

    Pathology & Biotechi

    Keywords - Diseasei

    Proto-oncogene

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11RemovedBy similarity
    Chaini2 – 509508Proto-oncogene tyrosine-protein kinase LCKPRO_0000088127Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Lipidationi2 – 21N-myristoyl glycineBy similarity
    Lipidationi3 – 31S-palmitoyl cysteineBy similarity
    Lipidationi5 – 51S-palmitoyl cysteineBy similarity
    Modified residuei102 – 1021PhosphoserineBy similarity
    Modified residuei159 – 1591PhosphothreonineBy similarity
    Modified residuei162 – 1621PhosphoserineBy similarity
    Modified residuei194 – 1941PhosphoserineBy similarity
    Modified residuei394 – 3941Phosphotyrosine; by autocatalysisBy similarity
    Modified residuei505 – 5051Phosphotyrosine; by CSKBy similarity

    Post-translational modificationi

    Autophosphorylated on Tyr-394, increasing enzymatic activity, this site is dephosphorylated by PTN22. Phosphorylated on Tyr-505 by CSK, decreasing activity. Dephosphorylated by PTPRC/CD45. Dephosphorylation at Tyr-394 by PTPN2 negatively regulates T-cells differentiation By similarity.By similarity
    Myristoylation is required prior to palmitoylation.By similarity
    Palmitoylation regulates subcellular location.By similarity

    Keywords - PTMi

    Lipoprotein, Myristate, Palmitate, Phosphoprotein

    Expressioni

    Tissue specificityi

    Expressed specifically in lymphoid cells.

    Developmental stagei

    Levels remain relatively constant throughout T-cell ontogeny.

    Interactioni

    Subunit structurei

    Binds to the cytoplasmic domain of cell surface receptors, such as AXL, CD2, CD4, CD5, CD8, CD44, CD45 and CD122. Also binds to effector molecules, such as PI4K, VAV1, RASA1, FYB and to other protein kinases including CDK1, RAF1, ZAP70 and SYK. Binds to phosphatidylinositol 3'-kinase (PI3K) from T-lymphocytes through its SH3 domain and to the tyrosine phosphorylated form of KHDRBS1/p70 through its SH2 domain. Interacts with SQSTM1. Interacts with phosphorylated LIME1. Interacts with CBLB and PTPRH. Interacts with RUNX3. Forms a signaling complex with EPHA1, PTK2B AND PI3-KINASE; upon activation by EFNA1 which may regulate T-lymphocytes migration. Associates with ZAP70 and RHOH; these interactions allow LCK-mediated RHOH and CD3 subunit phosphorylations in the presence of functional ZAP70 By similarity. Interacts with Saimiriine herpesvirus 2 TIP. Interacts with UNC119; this interaction plays a crucial role in activation of LCK By similarity.By similarity

    Structurei

    3D structure databases

    ProteinModelPortaliQ95KR7.
    SMRiQ95KR7. Positions 7-35, 65-509.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini61 – 12161SH3PROSITE-ProRule annotationAdd
    BLAST
    Domaini127 – 22498SH2PROSITE-ProRule annotationAdd
    BLAST
    Domaini245 – 498254Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni2 – 7271Interactions with CD4 and CD8By similarityAdd
    BLAST
    Regioni154 – 24289Interaction with PTPRHBy similarityAdd
    BLAST

    Domaini

    The SH2 domain mediates interaction with SQSTM1. Interaction is regulated by Ser-59 phosphorylation By similarity.By similarity

    Sequence similaritiesi

    Belongs to the protein kinase superfamily. Tyr protein kinase family.PROSITE-ProRule annotation
    Contains 1 protein kinase domain.PROSITE-ProRule annotation
    Contains 1 SH2 domain.PROSITE-ProRule annotation
    Contains 1 SH3 domain.PROSITE-ProRule annotation

    Keywords - Domaini

    SH2 domain, SH3 domain

    Phylogenomic databases

    HOVERGENiHBG008761.

    Family and domain databases

    Gene3Di3.30.505.10. 1 hit.
    InterProiIPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
    IPR000980. SH2.
    IPR001452. SH3_domain.
    IPR008266. Tyr_kinase_AS.
    IPR020635. Tyr_kinase_cat_dom.
    [Graphical view]
    PfamiPF07714. Pkinase_Tyr. 1 hit.
    PF00017. SH2. 1 hit.
    PF00018. SH3_1. 1 hit.
    [Graphical view]
    PRINTSiPR00401. SH2DOMAIN.
    PR00452. SH3DOMAIN.
    PR00109. TYRKINASE.
    SMARTiSM00252. SH2. 1 hit.
    SM00326. SH3. 1 hit.
    SM00219. TyrKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF50044. SSF50044. 1 hit.
    SSF55550. SSF55550. 1 hit.
    SSF56112. SSF56112. 1 hit.
    PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00109. PROTEIN_KINASE_TYR. 1 hit.
    PS50001. SH2. 1 hit.
    PS50002. SH3. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    Q95KR7-1 [UniParc]FASTAAdd to Basket

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    MGCGCSSHLE DDWMENIDVC ENCHYPIVPL DGKATLLFRN GSEVRDPLVR    50
    YEGSNPPASP LQDNLVIALH SYEPSHDGDL GFEKGEHLRI LEQNGEWWKA 100
    QSLTTGQEGF VPFNFVAKAN SLEPEPWFFK NLSRKDAERQ LLAPGNTHGS 150
    FLIRESESTA GSFSLSVRDF DQNQGEVVKH YKIRNLDNGG FYISPRITFS 200
    GLHELVRHYT NASDGLCTRL SRPCQTQKPQ KPWWEDEWEV PRETLKLVER 250
    LGAGQFGEVW MGYYNEHTKV AVKSLKQGSM SPDAFLAEAN LMKQLQHKRL 300
    VRLYAVVTEE PIYIITEYME NGSLVDFLKT PSGIKLTINK LLDMAAQIVE 350
    GMAFLEERNY IHRDLRAANI LVSDTLSCKI ADFGLARLIE DNEYTAREGA 400
    KFPIKWTAPE AINYGTFTIK SDVWSFGILM TEIVTHGRIP YPGMTNPEVI 450
    QNLERGYRMP RPDNCPEELY KLMMQCWRER PDDRPTFDYL RSVLEDFFTA 500
    TEGQYQPQP 509
    Length:509
    Mass (Da):58,253
    Last modified:January 23, 2007 - v3
    Checksum:i5088C6407D109519
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AJ277921 mRNA. Translation: CAC38871.1.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AJ277921 mRNA. Translation: CAC38871.1 .

    3D structure databases

    ProteinModelPortali Q95KR7.
    SMRi Q95KR7. Positions 7-35, 65-509.
    ModBasei Search...
    MobiDBi Search...

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Phylogenomic databases

    HOVERGENi HBG008761.

    Family and domain databases

    Gene3Di 3.30.505.10. 1 hit.
    InterProi IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
    IPR000980. SH2.
    IPR001452. SH3_domain.
    IPR008266. Tyr_kinase_AS.
    IPR020635. Tyr_kinase_cat_dom.
    [Graphical view ]
    Pfami PF07714. Pkinase_Tyr. 1 hit.
    PF00017. SH2. 1 hit.
    PF00018. SH3_1. 1 hit.
    [Graphical view ]
    PRINTSi PR00401. SH2DOMAIN.
    PR00452. SH3DOMAIN.
    PR00109. TYRKINASE.
    SMARTi SM00252. SH2. 1 hit.
    SM00326. SH3. 1 hit.
    SM00219. TyrKc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF50044. SSF50044. 1 hit.
    SSF55550. SSF55550. 1 hit.
    SSF56112. SSF56112. 1 hit.
    PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00109. PROTEIN_KINASE_TYR. 1 hit.
    PS50001. SH2. 1 hit.
    PS50002. SH3. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Downregulation of p56Lck tyrosine kinase activity in T cells of squirrel monkeys (Saimiri sciureus) correlates with the non-transforming and apathogenic properties of herpesvirus saimiri in its natural host."
      Greve T., Tamgueney G., Fleischer B., Fickenscher H., Broeker B.M.
      J. Virol. 75:9252-9261(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], ENZYME REGULATION, INTERACTION WITH SAIMIRIINE HERPESVIRUS 2 TIP.
      Tissue: T-cell.

    Entry informationi

    Entry nameiLCK_SAISC
    AccessioniPrimary (citable) accession number: Q95KR7
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: November 8, 2005
    Last sequence update: January 23, 2007
    Last modified: October 1, 2014
    This is version 91 of the entry and version 3 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Caution

    LCK seems to be active in all vertebrates, except in squirrel monkey T-cells, in which it is inactivated. The reason seems to be that squirrel monkeys are the natural host for Saimiriine herpesvirus 2, which is able to efficiently transform T-cells through a mechanism involving viral Tip/ host LCK interaction. Its inactivation may a mechanism that specifically counteracts the transformation effects of viral Tip.Curated

    Documents

    1. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3