Versatile communication strategies among tandem WW domain repeats

Abstract

Interactions mediated by short linear motifs in proteins play major roles in regulation of cellular homeostasis since their transient nature allows for easy modulation. We are still far from a full understanding and appreciation of the complex regulation patterns that can be, and are, achieved by this type of interaction. The fact that many linear-motif-binding domains occur in tandem repeats in proteins indicates that their mutual communication is used extensively to obtain complex integration of information toward regulatory decisions. This review is an attempt to overview, and classify, different ways by which two and more tandem repeats cooperate in binding to their targets, in the well-characterized family of WW domains and their corresponding polyproline ligands.

High-throughput methods for identification of protein-protein interactions involving short linear motifs

“…Although information on the binding specificities of individual domains may be available, it does not necessary reflect the specificity of the domains in the context of the full-length proteins. In addition, connected domains of a bait protein might bind to linked motifs in a target protein, which may increase the apparent affinity and enhance the specificity of the interactions [ 91 , 92 ]. Thus, dedicated approaches should be developed to account for such scenarios.…”

Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

“…Moreover, structural studies suggested that intermolecular interactions outside of core binding WW motifs could also affect their ability to bind to a particular partner [26]. Furthermore, as all mammalian NEDD4 E3s have tandem repeats of more than one WW domain, the WW domain-ligand interactions can be further fine-tuned by the versatile cooperativity among these tandem repeats [25].…”

“…The WW domains of NEDD4 E3s are believed to be the main mediators of their interactions with substrates and adaptors, primarily through association with PY motifs (PPxY or LPxY, x is any amino acid residue) on their interacting partners. In addition, WW domains have been shown to interact with phosphoserine or phosphothreonine residues, as well as with several non-canonical regions [25].…”

Regulation of gap junction intercellular communication by connexin ubiquitination: physiological and pathophysiological implications

“…The fact that the members of the NEDD4 family harbor multiple WW domains raises the possibility that tandem WW domain repeats may cooperate to enhance specificity and binding affinity [116]. For instance, the binding of the NEDD4 family member NEDD4-2 to its target SMAD2/3 first involves the phosphorylation-dependent binding of its WW3 domain to a site downstream of a PY motif, which positions the WW2 domain so that it can bind the PY motif, ultimately enhancing the total binding affinity [117].…”