Protein Disorder and Human Genetic Disease

Abstract

Abstract Intrinsically disordered proteins (IDPs) are biologically active proteins that lack stable structure under physiological conditions. They are involved in crucial biological functions related to regulation, recognition, signalling and control of various events in the cell. Misbehaviour of IDPs is commonly associated with various human diseases. IDPs represent a prominent part of the human diseasome, a network that links the human disease phenome (which includes all the human genetic diseases) with the human disease genome (which contains all the disease‐related genes), where they could be grouped into a unique entity, the human‐genetic‐disease‐associated unfoldome. The exonic single nucleotide variations (SNVs) may induce a significant change in the tendency of a protein region to be structured or disordered, thereby causing malfunction of such a protein and contributing to the disease risk. Therefore, IDPs are abundant in genetic diseases, play crucial roles in pathogenesis of these maladies, and clearly require special attention. Key Concepts: Intrinsically disordered proteins (IDPs) are common in various proteomes, where they constitute functionally broad and densely populated unfoldomes. IDPs have crucial biological functions and are responsible for regulation, recognition, signalling and control of various events in the cell. Dysfunction, dysregulation and misbehaviour of IDPs are related to the pathogenesis of various diseases. Mutations in IDPs are frequently associated with genetic diseases. Mutations affecting the potential post‐translational modification sites (which are frequently located within the intrinsically disordered regions) are often related to various diseases. A more‐detailed understanding of the roles of intrinsically disordered proteins in genetic diseases might provide a basis for rational drug design against them.