Specificity profiling of peptidebinding modules

Many intracellular proteins are composed of small, structurally discrete modules. In particular, scaffolding proteins that assemble signaling complexes often contain multiple peptide-binding modules. Thousands of peptide recognition domains are embedded in the human proteome, and these have been classified into over 70 distinct families (Pawson and Nash 2003). These families include domains that recognize phosphorylated peptides (SH2 and PTB), polyproline stretches (SH3 and WW) or C-terminal sequences (PDZ) (Figure 1.6). Phage-displayed peptide libraries have been used by many groups for specificity profiling of ligand binding to these types of domains (Sidhu et al. 2003a; Han et al. 2005).

Some of the earliest identified and characterized peptide-binding domains are SH3 domains, which due to their pivotal role in protein complexes have attracted considerable attention from molecular and cell biologists. SH3 domains consist of approximately 60 amino acids and are found in a wide variety of membrane-associated and cytoskeletal proteins, as well as in proteins with enzymatic activity and in adaptor proteins without catalytic activity (Macias et al. 2002). In general, SH3

FIGuRE 1.6 Structures of peptide-binding domains and peptide ligands. The domains are shown as gray surfaces, and the peptides are shown in dark gray. (A) The YAP65 WW domain bound to the peptide GTPPPPYTVG (PDB 1jmq) (Pires et al. 2001). (B) The Src SH3 domain bound to the peptide RALPPLP (PDB 1rlp) (Feng et al. 1994). (C) The Src SH2 domain bound to the phosphorylated peptide PQpYEEI (PDB 1sps) (Waksman et al. 1993). (D) The Erbin PDZ domain bound to the peptide TGWETWV (PDB 1n7t) (Skelton et al. 2003).

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