ZDHHC9 is a palmitoyl acyltransferase (PAT) whose substrates include small GTPases, such as H-Ras, N-Ras and R-Ras [, ], Lck kinase, and many transmembrane proteins and channels []. Mutations in ZDHHC9 cause mental retardation, X-linked, syndromic, ZDHHC9-related (MRXSZ) [].
Lck is a member of the Src non-receptor type tyrosine kinase family of proteins. CD4 and CD8 directly couple with Lck, and cross-linking of these receptors leads to Lck activation [, ]. The N-terminal tail of Lck is myristoylated and palmitoylated and it tethers the protein to the plasma membrane of the cell. Lck also contains an SH3 domain, an SH2 domain, and a C-terminal tyrosine kinase domain. Lck has 2 phosphorylation sites, the first an autophosphorylation site that is linked to activation of the protein and the second which is phosphorylated by Csk, which inhibits it. Lck is also inhibited by SHP-1 dephosphorylation and by Cbl ubiquitin ligase, which is part of the ubiquitin-mediated pathway []. This entry represents the SH2 domain of Lck.The Src non-receptor type tyrosine kinase (SFK) family members have an unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail. The SH2 domain of SFKs is involved in kinase autoinhibition and T-cell receptor signaling. The binding SH2 domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the SFKs [].
Lck is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lck is expressed in T-cellsand natural killer cells. It plays a critical role in T-cell maturation, activation, and T-cell receptor (TCR) signaling [, ]. Lck phosphorylates ITAM (immunoreceptor tyr activation motif) sequences on several subunits of TCRs, leading to the activation of different second messenger cascades. Phosphorylated ITAMs serve as binding sites for other signaling factor such as Syk and ZAP-70, leading to their activation and propagation of downstream events []. In addition, Lck regulates drug-induced apoptosis by interfering with the mitochondrial death pathway. The apototic role of Lck is independent of its primary function in T-cell signaling []. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction [, ].
Tyrosine-protein phosphatase non-receptor type 22 (PTPN22) acts as negative regulator of T-cell receptor (TCR) signalling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signalling molecules [].Variations of the PTPN22 gene affects the susceptibility of systemic lupus erythematosus (SLE) [].
This entry includes the single SH2 domain of SH2D2A. SH2D2A interacts with and modulates Lck activity [].In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites [, , ].
This domain is the C-terminal domain of the CD4 T cell receptor. The C-terminal domain is the cytoplasmic domain which relays the signal for T cell activation. This process involves co-receptor internalisation. This domain is involved in binding to the N-terminal of Lck co-receptor in a Zn2+ clasp structure.
Myelin is a product of myelinating cells: Schawnn cells in the peripheral nervous system (PNS) and oligodendrocytes in the central nervous system (CNS). The processes of these myelinating cells wrap around axon segments to form a sheath. This sheath possesses insulating properties, allowing rapid propagation of action potentials (the electrical signal propagated by nerve cells) between the myelinating cell intervening nodes. Without myelin insulation, axons would need a 10-30-fold increase in diameter to achieve comparable conduction velocities. At the onset of myelination, during development, large amounts of myelin-specific lipids and proteins are synthesised and transported to the developing myelin sheath. The major protein component of PNS and CNS myelin differs between the 2 nervous systems. However, some of the minor protein components, including the 4 transmembrane (TM)-domain-containing myelin and lymphocyte protein (MAL), are found in both systems. Outside the nervous system, MAL is also found in T-cells and some epithelial cells (e.g., kidney, stomach and thyroid) []. Glycosphingolipids are enriched in both epithelial cells and myelin, and are believed to decrease the permeability of lipid membranes to small molecules and increase the ability for membrane curvature. MAL co-purifies with glycosphingolipids in detergent-insoluble domains, suggesting a possible interaction. In Madin Darby Canine Kidney (MDCK) cells, MAL is found mainly in transport vesicles, and recent studies suggest that MAL is required for efficient vesicular transport of proteins across apical cell membranes []. In myelinating cells, MAL appears to play a similar role, interacting with glycosphingolipids to decrease membrane permeability; however, here this property most likely manifests itself as an improved insulating ability of the myelin []. In lymphocytes, however, MAL appears to act as a TM-linker protein in T-cell signal transduction, linking the cell surface glycosyl phosphatidylinositol anchored protein CD59 to the intracellular tyrosine kinase Lck [].
