SH3 Domains

Protein tyrosine kinases of the Src family are essential for cell development, growth, replication, adhesion, motility and neuronal function, and they are overexpressed in a wide number of human cancers. In the brain, the SH3 domain of Fyn tyrosine kinase was shown to interact with microtubule-associated Tau protein (Lee et al. 1998). Tau

Potential targets for PRD inhibitors

Potential targets for PRD inhibitors

Fig. 1 Pharmacological interference with PRM:PRD interaction in the context of disease. Shown are examples of cellular PRM:PRD interactions for every PRD fold family that represent pharmacological targets for drug development

is the major component of neurofibrillary tangles formed during Alzheimer's disease, and it is linked genetically to frontotemporal dementias (FTDP-17). Disease-related mutations in the Tau protein negatively affect the ability of the protein to bind and stabilize microtubuli (Hong et al. 1998). The various splice variants of Tau bind with different affinities to Fyn-SH3, and tyrosine phosphorylation was hypothesized to modulate these affinities (Bhaskar et al. 2005). Brain-specific inhibition of Fyn kinase is suggested to alter the onset of neuronal diseases, such as Alzheimer's (Chin et al. 2005), and the current data are sufficiently persuasive to suggest that the Fyn-SH3:Tau interaction has an impact on the Fyn-mediated progression of the disease.

Association of Src kinase family members with the cytoplasmic tails of transmembrane receptors is another common theme for these proteins, and many of the targeted receptors are involved in growth and differentiation of cells. For example, many of the T-cell-receptor-associated adhesion and co-stimulatory molecules are targeted by Src kinases, and in several cases this recruitment is mediated or at least complemented by the SH3 domain. Examples are CD28 and CD2, two molecules expressed specifically in T cells and NK cells. Both molecules harbor cytoplasmic PRM sites that are recognized by essential signaling molecules, such as Grb2 or the tyrosine kinase Itk in the case of CD28 (Okkenhaug and Rottapel 1998; Kim et al. 1998) and Fyn in the case of CD2 (Lin et al. 1998; Fukai et al. 2000). Antibodies against both of these molecules were shown to be effective in prolonged tolerance of transplants in cellular and animal models (Woodward et al. 1996; Rothstein and Sayegh 2003), and it is attractive to think of intracellular inhibition of the corresponding signaling pathways as a novel avenue of immune suppression. Fyn was shown to bind to several of the PRMs within the cytoplasmic domain of CD2. Interestingly, binding of the closely related Lck protein to the RPPPPGHR motif of the CD2 tail was much weaker and could be explained by a T97H exchange within the RT loop of the respective SH3 domain (Freund et al. 2002). The histidine in Lck forms an intramolecular hydrogen bond to aspartate 100, while the corresponding threonine residue in Fyn points towards the solvent. Thereby, a ligand arginine is able to insert into the specificity pocket of Fyn-SH3, but not Lck-SH3. This example shows that selective inhibition of SH3 domains may be achieved by exploiting small differences in the specificity determining regions of the respective SH3 domain.

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