Physicochemical properties of cells and their effects on intrisically disordered proteins (IDPs)

FRANCOIS-XAVIER THEILLET; ANDRÉS BINOLFI; TAMARA FREMBGEN-KESNER; KARAN HINGORANI; MOHONA SARKAR; CIARA KYNE; CONGGAN LI; PETER CROWLEY; LILA GIERASCH; GARY PIELAK; ADRIAN ELCOCK; ANNE GERSHENSON; PHILIPP SELENKO

CHEMICAL REVIEWS.

AMER CHEMICAL SOC

Lugar: Washington; Año: 2014 vol. 114 p. 6661 - 6714

0009-2665

*Theillet F-X and Andrés Binolfi ->  igual contribución.             It has long been axiomatic that a protein´s structure determines its function. Intrinsically disordered proteins (IDPs) and disordered protein regions (IDRs) defy this structure-function paradigm. They do not exhibit stable secondary and/or tertiary structures and exist as dynamic ensembles of interconverting conformers with preferred, non-random orientations. The concept of IDPs and IDRs as functional biological units was initially met with skepticism. For a long time, disorder, intuitively implying chaos, had no place in our perception of orchestrated molecular events controlling cell biology. Over the past years, however, this notion has changed. Aided by findings that structural disorder constitutes a ubiquitous and abundant biological phenomenon in organisms of all phyla, and that it is often synonymous with function, disorder has become an integral part of modern protein biochemistry. Disorder thrives in eukaryotic signaling and functions as a prominent player in many regulatory processes. Disordered proteins and protein regions determine the underlying causes of many neurodegenerative disorders and constitute the main components of amyloid fibrils. Additionally, because of their widespread role in cell signaling they are also involved in pathological processes leading to cancer, diabetes or cardiovascular diseases. Research into disordered proteins produced significant findings and established important new concepts. On the structural side, novel experimental and computational approaches identified and described disordered protein ensembles and led to terms such as secondary structure propensities, residual structural features and transient long-range contacts. The discovery of coupled folding-and-binding reactions defined the paradigm of disorder-to-order transitions and high-resolution insights into the architectures of amyloid fibrils were obtained. On the biological side, we learned about the unexpected intracellular stability of disordered proteins, their roles in integrating post-translational protein modifications in cell signaling and about their functions in regulatory processes ranging from transcription to cell fate decisions. One open question remaining to be addressed is how these in vitro structural insights relate to biological in vivo effects. How do complex intracellular environments modulate the in vivo properties of disordered proteins and what are the implications for their biological functions? Here, we attempt to answer this question by reviewing the physical and biological properties of intracellular environments in relation to structural and functional parameters of disordered proteins. Specifically, we discuss how IDPs may experience in vivo environments differently to ordered proteins. To this end, we provide a description of the compositional and physical parameters of the cellular milieu and their effects on ordered and disordered proteins (chapter 2). We evaluate how biological processes may act differently on ordered and disordered proteins (chapter 3) and discuss how combined physical and biological contributions modulate the intracellular aggregation behavior of IDPs (chapter 4). Finally, we review theoretical and experimental approaches to study the structural and functional properties of disordered proteins in cells (chapter 5).