Dynamic conformational flexibility and molecular interactions of intrinsically disordered proteins
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Review Dynamic conformational flexibility and molecular interactions of intrinsically disordered proteins ANIL BHATTARAI and ISAAC ARNOLD EMERSON* Bioinformatics Programming Laboratory, Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore 632 014, India *Corresponding author (Email, [email protected]) MS received 26 July 2019; accepted 1 December 2019 Intrinsically disordered proteins (IDPs) are highly flexible and undergo disorder to order transition upon binding. They are highly abundant in human proteomes and play critical roles in cell signaling and regulatory processes. This review mainly focuses on the dynamics of disordered proteins including their conformational heterogeneity, protein–protein interactions, and the phase transition of biomolecular condensates that are central to various biological functions. Besides, the role of RNA-mediated chaperones in protein folding and stability of IDPs were also discussed. Finally, we explored the dynamic binding interface of IDPs as novel therapeutic targets and the effect of small molecules on their interactions. Keywords. separation
aggregation; chaperone; intrinsically disordered proteins; protein–protein interactions; phase
1. Introduction Proteins are dynamic entities that fold into their native conformations to function. Some proteins are biologically active even in an unfolded state, and these are intrinsically disordered proteins (IDPs) (Berlow et al. 2015). IDPs are proteins that lack secondary and or tertiary structures under native physiological conditions in vitro, but they are biologically active. These proteins are found as dynamic ensembles of high conformational heterogeneity (Kikhney and Svergun 2015). IDPs have different frequencies of amino acids that determine their structure-function relationship. They are depleted in order-promoting residues (low hydrophobicity and hold a high proportion of disorderpromoting residues (high net charges) (Wright and Dyson 2015). High net charges in IDPs can change protein conformations by electrostatic repulsion (Liu et al. 2014; Marsh and Forman-Kay 2010). A few hydrophobic residues in IDPs mediate protein–protein interactions with high specificity and low-affinity (Dunker et al. 2001). IDPs form complexes with other proteins and they transit from disorder to order through http://www.ias.ac.in/jbiosci
the coupled folding and binding. The coupled folding and binding of IDPs depends on thermodynamic properties such as a change in Gibbs free energy (Schreiber and Fersht 1996) as well as physiological factors of the system (Dogan et al. 2014). Some IDPs retain their conformational heterogeneity and form dynamic complexes (Tompa and Fuxreiter 2008). Despite the lack of fixed and ordered structures, IDPs are highly abundant and exhibit different biological functions. The different frequency of amino acid composition and unique pattern of point mutations (including higher insertion and d
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