Intrinsic disorder in scaffold proteins: Getting more from less

Abstract

Regulation, recognition and cell signaling involve the coordinated actions of many players. Signaling scaffolds, with their ability to bring together proteins belonging to common and/or interlinked pathways, play crucial roles in orchestrating numerous events by coordinating specific interactions among signaling proteins. This review examines the roles of intrinsic disorder (ID) in signaling scaffold protein function. Several well-characterized scaffold proteins with structurally and functionally characterized ID regions are used here to illustrate the importance of ID for scaffolding function. These examples include scaffolds that are mostly disordered, only partially disordered or those in which the ID resides in a scaffold partner. Specific scaffolds discussed include RNase, voltage-activated potassium channels, axin, BRCA1, GSK-3beta, p53, Ste5, titin, Fus3, BRCA1, MAP2, D-AKAP2 and AKAP250. Among the mechanisms discussed are: molecular recognition features, fly-casting, ease of encounter complex formation, structural isolation of partners, modulation of interactions between bound partners, masking of intramolecular interaction sites, maximized interaction surface per residue, toleration of high evolutionary rates, binding site overlap, allosteric modification, palindromic binding, reduced constraints for alternative splicing, efficient regulation via posttranslational modification, efficient regulation via rapid degradation, protection of normally solvent-exposed sites, enhancing the plasticity of interaction and molecular crowding. We conclude that ID can enhance scaffold function by a diverse array of mechanisms. In other words, scaffold proteins utilize several ID-facilitated mechanisms to enhance function, and by doing so, get more functionality from less structure.

HIV-1 Tat recruits transcription elongation factors dispersed along a flexible AFF4 scaffold

“…The long, unstructured nature of AFF4 implies that flexibility may be an important organizational principle required for SEC function. This flexibility, as in other intrinsically disordered scaffolds (39,40), likely modulates binding affinity, allows the coordination of multiple components over long distances, and provides mechanisms for dynamic adaptation to new binding partners and spatial requirements.…”

“…A major challenge in defining the functions of natively unstructured proteins is the identification of interaction domains (39). Minimal AFF4 protein interaction sites mapped to the few short, hydrophobic segments in the scaffold sequence.…”

Loss of EBP50 stimulates EGFR activity to induce EMT phenotypic features in biliary cancer cells

“…We show that gefitinib inhibition of EGFR phosphorylation was greater in EBP50-silenced cells than in controls, suggesting that in these cells EGFR-binding site for ATP was more accessible to gefitinib. Scaffold proteins have been shown to promote conformational changes of their binding partners (Dard and Peter, 2006;Cortese et al, 2008). The fact that in EBP50-silenced cells, EGFR was more accessible, both to its ligand(s) and to gefitinib, supports a scenario in which EBP50 induces masking/unmasking of intramolecular interaction sites by altering EGFR conformation.…”

Exceptionally abundant exceptions: comprehensive characterization of intrinsic disorder in all domains of life

“…Although IDPs and intrinsically disordered regions (IDRs) in proteins are devoid of stable 3D-structures, they possess crucial biological functions and play multiple important roles in living organisms. In fact, the conformational plasticity associated with intrinsic disorder provides IDPs/IDRs with a wide spectrum of exceptional functional advantages over the functional modes of ordered proteins and ordered protein domains [1,2,[5][6][7][8][9][10][11][12][13][14][15][16][17]. For example, the high accessibility of sites within the disordered proteins simplifies their posttranslational modifications, such as phosphorylation, acetylation, lipidation, ubiquitination, sumoylation, etc., allowing for modulation of their biological functions [5].…”