TY - JOUR

T1 - Interactions by Disorder - A Matter of Context

AU - Bugge, Katrine

AU - Brakti, Inna

AU - Fernandes, Catarina B.

AU - Dreier, Jesper E.

AU - Lundsgaard, Jeppe E.

AU - Olsen, Johan G.

AU - Skriver, Karen

AU - Kragelund, Birthe B.

N1 - Copyright © 2020 Bugge, Brakti, Fernandes, Dreier, Lundsgaard, Olsen, Skriver and Kragelund.

PY - 2020

Y1 - 2020

N2 - Living organisms depend on timely and organized interactions between proteins linked in interactomes of high complexity. The recent increased precision by which protein interactions can be studied, and the enclosure of intrinsic structural disorder, suggest that it is time to zoom out and embrace protein interactions beyond the most central points of physical encounter. The present paper discusses protein-protein interactions in the view of structural disorder with an emphasis on flanking regions and contexts of disorder-based interactions. Context constitutes an overarching concept being of physicochemical, biomolecular, and physiological nature, but it also includes the immediate molecular context of the interaction. For intrinsically disordered proteins, which often function by exploiting short linear motifs, context contributes in highly regulatory and decisive manners and constitute a yet largely unrecognized source of interaction potential in a multitude of biological processes. Through selected examples, this review emphasizes how multivalency, charges and charge clusters, hydrophobic patches, dynamics, energetic frustration, and ensemble redistribution of flanking regions or disordered contexts are emerging as important contributors to allosteric regulation, positive and negative cooperativity, feedback regulation and negative selection in binding. The review emphasizes that understanding context, and in particular the role the molecular disordered context and flanking regions take on in protein interactions, constitute an untapped well of energetic modulation potential, also of relevance to drug discovery and development.

AB - Living organisms depend on timely and organized interactions between proteins linked in interactomes of high complexity. The recent increased precision by which protein interactions can be studied, and the enclosure of intrinsic structural disorder, suggest that it is time to zoom out and embrace protein interactions beyond the most central points of physical encounter. The present paper discusses protein-protein interactions in the view of structural disorder with an emphasis on flanking regions and contexts of disorder-based interactions. Context constitutes an overarching concept being of physicochemical, biomolecular, and physiological nature, but it also includes the immediate molecular context of the interaction. For intrinsically disordered proteins, which often function by exploiting short linear motifs, context contributes in highly regulatory and decisive manners and constitute a yet largely unrecognized source of interaction potential in a multitude of biological processes. Through selected examples, this review emphasizes how multivalency, charges and charge clusters, hydrophobic patches, dynamics, energetic frustration, and ensemble redistribution of flanking regions or disordered contexts are emerging as important contributors to allosteric regulation, positive and negative cooperativity, feedback regulation and negative selection in binding. The review emphasizes that understanding context, and in particular the role the molecular disordered context and flanking regions take on in protein interactions, constitute an untapped well of energetic modulation potential, also of relevance to drug discovery and development.

U2 - 10.3389/fmolb.2020.00110

DO - 10.3389/fmolb.2020.00110

M3 - Review

C2 - 32613009

VL - 7

JO - Frontiers in Molecular Biosciences

JF - Frontiers in Molecular Biosciences

SN - 2296-889X

M1 - 110

ER -