Abstract
Our notions of protein function have long been determined by the protein structure-function paradigm. However, the idea that protein function is dictated by a prerequisite complementarity of shapes at the binding interface is becoming increasingly challenged. Interactions involving intrinsically disordered proteins (IDPs) have indicated a significant degree of disorder present in the bound state, ranging from static disorder to complete disorder, termed 'random fuzziness'. This review assesses the anatomy of an IDP and relates how its intrinsic properties permit promiscuity and allow for the various modes of interaction. Furthermore, a mechanistic overview of the types of disordered domains is detailed, while also relating to a recent example and the kinetic and thermodynamic principles governing its formation.
Highlights
The historic protein structure–function paradigm dictates that in order for a protein to function, it must adopt a specific three-dimensional structure
The 1 : 1 complex formed between E-cad and β-cat was monitored by nanosecond FCS and sm-FRET studies to determine a relative binding affinity, dynamics and to define parameters used for CG molecular dynamics (MD) simulations
The protein structure–function paradigm indicates that the function of a protein is encoded within complementary binding interfaces
Summary
The historic protein structure–function paradigm dictates that in order for a protein to function, it must adopt a specific three-dimensional structure. Over the past three decades, it has become apparent that a large percentage of any organism’s proteome consists of proteins or protein regions that lack any form of well-defined secondary structure [4] These proteins are said to be intrinsically disordered. The conformational plasticity of an individual IDP allows for a range of secondary structures to be induced in the bound state of its promiscuous interactions; an example is the tumour suppressor protein, p53, which has over 500 interaction partners on the STRING database and adopts an array of structures in complex [10]. While basic secondary structure may be induced upon the binding of an IDP to a folded partner, the enthalpic contributions of binding may not be sufficient to pay the entropic penalty, and the protein will exhibit both ordered and disordered transitions in the bound state. A description will be offered on how the anatomy of an IDP enables the formation of these interaction domains, along with providing the kinetic and thermodynamic principles governing their formation
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