Actin-cytoskeletal rearrangement

FIGURE 7-4 Selected adaptors that participate in lymphocyte activation. On the left, LAT, an integral membrane protein that functions as an adaptor, and two cytosolic adaptors, GADS and SLP-76, are shown in a nonactivated T cell. On the right, after T cell activation, LAT is tyrosine phosphory-lated and is shown to have recruited PLCy and the GADS adaptor, both of which contain SH2 domains. A proline-rich amino acid stretch in SLP-76 associates with an SH3 domain of GADS, and tyrosine-phosphorylated SLP-76 recruits Vav.

of a Syk family kinase to an antigen receptor by means of a specific SH2 domain-phosphotyrosine interaction is a key step in antigen receptor activation.

SH3 domains are also about 100 amino acids in length, and they help mediate protein-protein interactions by binding to proline-rich stretches in certain proteins. Another type of modular domain, called a pleckstrin homology (PH) domain, can recognize specific phospho-lipids. The PH domains in a number of signaling molecules including the TEC family tyrosine kinase Btk, recognize phosphatidylinositol trisphosphate (PIP3), a lipid moiety on the inner leaflet of the plasma membrane.

Adaptor proteins function as molecular hubs that physically link different enzymes and promote the assembly of complexes of signaling molecules. Adaptors may be integral membrane proteins like LAT (linker for the activation of T cells) (Fig. 7-4), or they may be cytosolic proteins such as BLNK (B cell linker), SLP-76 (SH2 domain-containing linker protein of 76 kD), and GADS (Grb-2-related adaptor protein downstream of Shc). A typical adaptor may contain a few specific domains that mediate protein-protein interactions, such as SH2 and SH3 domains, among others (there are many more types of modular domains not mentioned here). Adaptors may also contain some proline-rich stretches (that can bind other proteins that contain SH3 domains), and they also often contain critical tyrosine residues that may be phos-phorylated by tyrosine kinases. The amino acid residues that are close to a tyrosine moiety that is phosphorylated determine which specific SH2 domains may bind that site. For instance, an adaptor with a YxxM motif (where Y represents tyrosine, M represents methionine, and x refers to any amino acid) will bind an SH2 domain in the lipid kinase phosphatidylinositol 3-kinase (PI3-kinase). The same adaptor protein may recruit a tyrosine kinase with a specific SH3 domain to a proline-rich stretch, and tyrosine phosphorylation of the adaptor may thus result in a tyrosine kinase and PI3-kinase being perched next to each other, resulting in the phosphorylation and activation of PI3-kinase. Signal transduction can therefore be visualized as a kind of social networking phenomenon. An initial signal (tyrosine phosphoryla-tion, for instance) results in proteins being brought close to one another at designated hubs (adaptors), resulting in the activation of specific enzymes that eventually influence the nuclear localization or activity of specific downstream transcription factors or induce other cellular events, such as actin polymerization.

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