Intrinsically Disordered Proteins in Human Diseases: Introducing the D²Concept

Abstract

Intrinsically disordered proteins (IDPs) lack stable tertiary and/or secondary structures under physiological conditions in vitro. They are highly abundant in nature and their functional repertoire complements the functions of ordered proteins. IDPs are involved in regulation, signaling, and control, where binding to multiple partners and high-specificity/low-affinity interactions play a crucial role. Functions of IDPs are tuned via alternative splicing and posttranslational modifications. Intrinsic disorder is a unique structural feature that enables IDPs to participate in both one-to-many and many-to-one signaling. Numerous IDPs are associated with human diseases, including cancer, cardiovascular disease, amyloidoses, neurodegenerative diseases, and diabetes. Overall, intriguing interconnections among intrinsic disorder, cell signaling, and human diseases suggest that protein conformational diseases may result not only from protein misfolding, but also from misidentification, missignaling, and unnatural or nonnative folding. IDPs, such as alpha-synuclein, tau protein, p53, and BRCA1, are attractive targets for drugs modulating protein-protein interactions. From these and other examples, novel strategies for drug discovery based on IDPs have been developed. To summarize work in this area, we are introducing the D2 (disorder in disorders) concept.

From protein sequence to dynamics and disorder with DynaMine

“…In all, the use of DynaMine opens up the enormous pool of available protein sequences lacking structure information for similar dynamics analysis. It may also give us important clues on diseases, in which the mutations causing critical changes in the structure and/or dynamics of IDPs lead to alterations in function and/or aggregation of the protein 43,44 .…”

The human RBPome: From genes and proteins to human disease

“…Intrinsically disordered proteins are characterised by a structural feature called "Intrinsic disorder" that enables them to participate in varied cellular functions [41,42]. RBPs being diverse structurally and functionally, are known to be highly disordered [43,44].…”

Side-Chain Interactions Form Late and Cooperatively in the Binding Reaction between Disordered Peptides and PDZ Domains

“…1,2 Experimental mechanistic studies on disordered proteins have appeared only recently, for example refs. [3][4][5][6][7][8][9][10] Given the fact that they make up a large portion of the proteins encoded by the eukaryotic genome, as well as their frequent association with diseases, 11,12 understanding the role of disorder in protein-protein recognition is a key problem in modern structural biology. In particular, mechanistic data are scarce.…”