%0 Journal Article
%T Proline Rich Motifs as Drug Targets in Immune Mediated Disorders
%A Mythily Srinivasan
%A A. Keith Dunker
%J International Journal of Peptides
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/634769
%X The current version of the human immunome network consists of nearly 1400 interactions involving approximately 600 proteins. Intermolecular interactions mediated by proline-rich motifs (PRMs) are observed in many facets of the immune response. The proline-rich regions are known to preferentially adopt a polyproline type II helical conformation, an extended structure that facilitates transient intermolecular interactions such as signal transduction, antigen recognition, cell-cell communication and cytoskeletal organization. The propensity of both the side chain and the backbone carbonyls of the polyproline type II helix to participate in the interface interaction makes it an excellent recognition motif. An advantage of such distinct chemical features is that the interactions can be discriminatory even in the absence of high affinities. Indeed, the immune response is mediated by well-orchestrated low-affinity short-duration intermolecular interactions. The proline-rich regions are predominantly localized in the solvent-exposed regions such as the loops, intrinsically disordered regions, or between domains that constitute the intermolecular interface. Peptide mimics of the PRM have been suggested as potential antagonists of intermolecular interactions. In this paper, we discuss novel PRM-mediated interactions in the human immunome that potentially serve as attractive targets for immunomodulation and drug development for inflammatory and autoimmune pathologies. 1. Protein-Protein Interactions Protein-protein interactions (PPIs) are critical for most biological functions and cellular processes [1, 2]. Under appropriate environmental conditions, the PPIs take place through an interface governed by shape, chemical complementarity, and flexibility of the interacting molecules. Different types of PPIs have been described. Homo- or heterologous oligomeric PPI complexes represent isologous or heterologous association of identical protein units. PPI complexes of interdependent protomer units are referred to as obligate complexes as opposed to nonobligate complexes that occur independently [3, 4]. The strength of PPI is represented by the dissociation constant (KD) expressed in molar concentration and derived from the ratio between the dissociation and association rate constants. Based on duration and affinity, PPIs can be classified as strong interactions that exhibit KD values with ¦ÌM concentrations and weak or transient interactions with values in the mM or higher concentrations. Transient PPIs are further divided into strong and weak transient interactions.
%U http://www.hindawi.com/journals/ijpep/2012/634769/