Variants of intrinsic disorder in the human proteome

TL;DR

This study classifies human proteins based on their disorder content, revealing that proteins with disordered regions are functionally and disease-related distinct groups, with implications for understanding disease mechanisms.

Contribution

It introduces a clear operational framework for categorizing disordered proteins and analyzes their distribution and potential roles in human diseases.

Findings

IDRPs resemble NDPs in function and structure

IDPs are more associated with complex diseases like cancer and neurodegeneration

Disorder variants have distinct prevalence in disease-related proteins

Abstract

In this paper we propose a straightforward operational definition of variants of disordered proteins, taking the human proteome as a case study. The focus is on a distinction between mostly unstructured proteins and proteins which contain long unstructured regions accommodated in an overall folded structure. In particular we distinguish: i) Not disordered proteins (NDPs), that either have all their residues ordered or do not have disordered segments longer than 30 residues nor more than 30% of disordered residues; ii) Proteins with intrinsically disordered regions (IDRPs), that have at least one disordered domain longer than 30 residues, but disordered in less than 30% of their residues; iii) Proteins that are intrinsically disordered (IDPs), that have both at least one disordered segment longer than 30 residues and that are disordered on more than 30% of their residues; iv) Proteins with fragmented disorder (FRAG_IDPs), that do not have a disordered fragment longer than 30 residues but that, nevertheless, have at least 30% or more of their residues predicted as disordered. The potential use of these variants is checked over several groups of disease-related proteins. Our main conclusions point out that IDRPs are more similar to NDPs than to IDPs. IDRPs and NDPs have a similar functional repertoire and probably share a lock-and-key mechanism of interaction with substrates. IDRPs and IDPs are differently present among human disease-related proteins. IDRPs probably do not play a specific role in the development of complex diseases, since their frequency is similar in disease-related proteins and in the entire human proteome. IDPs can play a role in the emergence of cancer, neurodegenerative, thyroid and liver disease.