Abstract

The structure-function paradigm has guided investigations into the molecules involved in cellular signalling for decades. The peripheries of this paradigm, however, start to unravel when considering the co-operation between proteins and the membrane in signalling processes. Intrinsically disordered regions hold distinct advantages over folded domains in terms of their binding promiscuity, sensitivity to their particular environment and their ease of modulation through post-translational modifications. Low sequence complexity and bias towards charged residues are also favourable for the multivalent electrostatic interactions that occur at the surfaces of lipid bilayers. This review looks at the principles behind the successful marriage between protein disorder and membranes in addition to the role of this partnership in modifying and regulating signalling in cellular processes. The HVR (hypervariable region) of small GTPases is highlighted as a well-studied example of the nuanced role a short intrinsically disordered region can play in the fine-tuning of signalling pathways.

Highlights

  • The discovery and characterization of intrinsically disordered proteins and regions (IDPs and intrinsically disordered region (IDR)) shattered the long-held structure-function paradigm

  • The energy landscape of disordered proteins is characterized by multiple, shallow minima, which correspond to a number of different states that the protein can sample without energetic penalty

  • This review has focussed on the interplay between disordered regions and the membrane and how this dynamic cross-talk is integral to cell signalling

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Summary

Introduction

The discovery and characterization of intrinsically disordered proteins and regions (IDPs and IDRs) shattered the long-held structure-function paradigm. Part 1 of 2 (A) Disordered regions can fold upon membrane binding, forming amphipathic helices, with the hydrophobic face adsorbed into the membrane and polar/charged residues exposed to the lipid heads and the aqueous environment.

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