Adaptor Domains as Key Components of PPIMediated Signal Complex Formation

The potential to interfere with PPIs in multi-protein signaling complexes is of great importance both for the understanding of cell physiology and for the development of novel disease treatments. Modular proteins involved in signal transduction utilize highly conserved non-catalytic adaptor domains that mediate PPIs during the formation of multi-protein signaling complexes. In general, these adaptor domains must fulfill certain requirements to exert their binding function. Firstly, the structural properties of the domain have to ensure the incorporation into a limited set of macromolecular complexes. The limited specificity of the adaptor domains may well be complemented by additional contacts of surrounding PPIs (Zarrinpar et al. 2003a). Secondly, the interactions have to be reversible to allow the dissociation of the complex as soon as a certain stimulus occurs or is removed. The requirement for relatively high off rates implies that PPIs are often characterized by modest affinities in the low micromolar to low millimolar range. Recognition of short, solvent-exposed peptide sequences mostly fulfills this prerequisite. Correspondingly, many adaptor domains have been shown to bind to small synthetic peptides containing a characteristic core motif, flanked by residues that are responsible for a certain degree of specificity. A large number of different families of PPI domains have been described. In many cases, the domains recognize target core motifs containing phosphorylated residues. Paradigmatic examples are the Src-homology 2 (SH2) and phosphotyrosine-binding (PTB) domains which bind core sequence motifs containing phosphorylated tyrosines (Vetter and Zhang 2002). Among others, forkhead-associated (FHA) domains are often utilized by eukaryotic proteins for the recognition of phosphoserine- and phosphothreonine-containing peptides (Williams, Bernstein et al. 2005). Another well-known family of protein-interaction domains is the postsynaptic density/disc-large/ZOl (PDZ) family that recognizes and binds the extreme C-terminal sequence of their binding partners (Dev 2004). An important class of PPI modules binds to solvent-exposed regions within their respective target proteins containing proline-rich motifs (PRMs). These PRM-recognition domains (PRDs) are especially abundant in higher eukaryotes and are particularly interesting in the context of multi-component signaling events that govern cellular behavior in its full complexity. The functional context of PRDs, their recognition codes and the regulation of PRD-binding function will be described in the following. Subsequently, efforts to target the respective interaction sites by small organic compounds will be discussed.

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