LCK PROTEIN TYROSINE KINASE
Structure and Location
Chime figure of Lck
Structure and Location
Lck protein tyrosine kinase is a kinase of the Src-family involved in the T cell signal transduction pathway which leads to mitosis and proliferation of memory and effector T cells (Janeway et al., 1999). It is coded for by chromosome 4 in mice and the 1p35-p32 segment in humans It is coded for by chromosome 4 in mice and the 1p35-p32 segment in humans ( <www.Lckgene >).It is associated with the cytoplasmic domain of CD4 and binds CD8 in the tail of its alpha chain (ibid). However, its activation occurs primarily after ligation with CD4,and a minority of CD8 are associated with Lck (Delves et al., 1998). Binding with CD8 is thought to induce more efficient T cell receptor signaling in effector and memory cells, where Lck is found primarily in the cytoplasmic domains with the co-receptor, as opposed to naïve T cells, in which Lck is distributed throughout the cytosol (Bachmann et al.,1999). Lck itself has three domains, SH3, SH2, and the kinase domain, which are involved in the regulation of the catalytic activity of the protein (Yamaguchi et al., 1996). It is thought that the amino terminal of Lck is associated with the CD4 through the formation of ionic bonds between its negatively charged amino acids and the basic residues in the cytoplasmic domain of the co-receptor, anchoring the CD4/ Lck complex (Delves et al., 1998).
Figure of an Src family kinase
It is generally agreed that Lck is activated upon the clustering of the CD4 or CD8 co-receptor cross-linking with the T cell receptor and MHC complex. Some studies suggest that enzyme activation does not require the binding of the co-receptor to the MHC, because some Lck associates the CD8 directly with the T cell receptor, allowing for higher affinity receptors, as in memory and effector cells (Bachmann et al., 1999). It is also possible that activation of Lck has more to do with the surrounding membrane environment than the clustering of co-receptors with T cell receptor and MHC (Ilangumaran et al., 1999). The activated Lck phosphorylates the ITAMS on the CD3 gamma, delta, epsilon, and zeta chains, allowing them to bind the kinase ZAP-70, which Lck then activates by phosphorylation , and the signal cascade continues (Janeway et al., 1999). The activation of Lck also depends on the proteins Csk and CD45, which are thought to inhibit and regulate its catalytic activity by phosphorylation and dephosphorylation, respectively (ibid.) If the Tyr-505 region in the carboxyl terminus of the kinase domain is phosphorylated, this portion of the Lck binds to its own SH2 and the protein becomes inactive, not allowing the kinase to make movement necessary for catalytic activity. However, autophosphorylation at Tyr-394 in the activation loop of Lck causes it to become activated, and the signal can proceed ( Eck et al., 1994). While it is possible that CD45 is required to maintain activation of Lck (Delves et al., 1998), some studies in which CD45 was removed and the protein tyrosine kinase activity remained uncompromised suggest that CD45 is not essential for enzyme activity (Ilangumaran et al., 1999). Ilangumaran postulates that intermittent opening and closing of the kinase domain allows some activation, and that some movements which open the kinase from its locked conformation with the carboxy-terminal Tyr-505 also activate it (ibid.) Another study demonstrates that activation of Lck by phosphorylation of Tyr-394 is dominant over the inhibition induced by phosphorylation of Tyr-505 (Eck et al., 1994).
Mice with deficiencies in Lck or having dominant negative transgenes for Lck show an arrest in T cell development (Weiss et al., 1994). In T cell differentiation, Lck is necessary to halt Beta chain rearrangement and induce cell proliferation, so its absence results in a cessation of development before double negative stage, after Beta-chain rearrangement and cell surface expression, but before alpha-chain rearrangement (Janeway et al., 1999). However, it appears as though Lck is not essential for thymocyte development, because some T cells mature despite this kinase deficiency (ibid.). This conclusion is also supported by the introduction of a CD8 transgene with a mutated Lck binding site into mice, which reduced the number of mature CD8 cells by half, but did not restrict the T cell receptor repertoire (Delves et al., 1998). While not essential to all T cell proliferation, its absence does result in a severe depletion of developed T cell lymphocytes (Janeway et al., 1999).
Figure of Lck
The Kinase Domain Of Human Lymphocyte Kinase (Lck), Activated Form (Auto-Phosphorylated On Tyr394).
< http://www.ncbi.nlm.nih.gov/Structure/ >. MMDB Id: 6883, PDB Id:3LCK
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