Sequence Peptide Motifs

Mrksich, M., M.E. Parks, and P.B. Dervan. Hairpin peptide motif A new class of oligopeptides for sequence-specific recognition in the minor-groove of double-helical DNA. J. Am. Chem. Soc. 1994, 116, 7983-7988. 

Structure-activity relationship studies investigating the antimicrobial activities of host defense peptides have primarily sought the characterization of the specific sequence/structural motifs that dictate antimicrobial and cytotoxic activities. Perhaps unsurprisingly these activities appear to be dictated by a delicate balance of cationicity, hydrophobicity, amphipathicity, and ultimately the structural characteristics of the peptides. 

Early work in the field has established the synthetic strategies and analytical tools for such class of libraries (for reviews see refs[111 112 456]). As listed in Table 13, the first generation of cyclic peptide libraries focused on biologically active sequences such as the cell adhesion RGD motif, the antileukemic heptapeptide stylostatin, or endothelin antagonists, but also on metal-binding sequence motifs and on the de novo discovery of bioactive cyclic peptides without sequence-biased motifs. Moreover, synthetic questions were addressed such as the sequence dependency of peptide cyclization reactions (see Table 13). 

The selectivity of peptide motifs for certain metals comes from the coordinating contribution from amino acid side chains, the common coordination number of the metal, hardness/softness of the metal ion, ligand field stabilisation effects and the hardness/softness of any coordinating side chains of the amino acid sequence. An example of the influence of side chains and the importance of the position of the side chain comes from the tripeptides Gly-Gly-His, also known as copper binding peptide. The side chain imidazole ring of the His residue has a very efficient nitrogen donor (the imidazole N), which can form a tetradentate chelate ring for coordination as in Scheme 10.3. 

A large number of gene sequences are now available for HMW subunits, showing that they typically comprise between 630 and 820 amino acids, with M, ranging from 67,500 to 88,000 (Shewry et al. 2003). Their sequences can be divided into three domains, an extensive central domain consists of repeated sequences based on two or three peptide motifs, hexapeptides (consensus Pro.Gly.Gln.Gly.Gln.Gln), nonapeptides (consensus Gly.Tyr.Tyr.Pro.Thr.Ser.Pro/Leu.Gln.Gln) and tripeptides (consensus Gly.Gln.Gln) which vary in length from 420 to 700 residues. These repetitive domains are flanked by shorter non-repetitive domains which vary in length between 81 to 104 residues at the A-terminus and 42 residues at the C-terminus. The non-repetitive N- and C-terminal domains contain most or all of the cysteine residues available for inter-chain covalent bonding. 

The MAPKs are protein kinases activated by growth factors, hormones, cytokines, and environmental stresses. One or more MAPKs are activated by almost every cell stimulus. The first MAPKs sequenced, Ksslp and Fus3p, are also the kinases most similar to mammalian ERKl/2 and were found in the pheromone response pathway of the budding yeast nearly 20 years ago (8). Subsequently, activities found in mammalian cells that favored Ser/Thr residues followed by Pro in substrates were purified and were shown to be mammalian MAPKs. More than a dozen mammalian MAPKs have now been identified. The hallmark of the MAPK family is the hi-peptide motif (Thr-Xxx-Tyr) located within the activation loop (T-loop) of the kinase domain, which contains the two sites phosphorylated to activate the kinases (2-9). Based on the canonical TZY motif and other features of the primary sequence, MAPKs are classified even more into three major subgroups the extracellular... 

Falk K, Rotzschke O, Stevanovic S, Jung G, Rammensee HG (1994) Pool sequencing of natural HLA-DR, DQ and DP ligands reveals detailed peptide motifs, constraints of processing, and general rules, Immunogenetics 39 230-242. 

Peptide motifs. Proteins with certain homologous sequences are rapidly degraded. For example, proteins that have extended sequences containing proline, glutamate, serine, and threonine have half-lives of less than 2 hours. (PEST sequences are named for the one-letter abbreviations for these amino acids. See Table 5.1.) The cyclin destruction box is a set of homologous nine-residue sequences near the N-terminus of cyclins that ensures rapid ubiquination. 

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