The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease

Abstract

In the 1960s, Christian Anfinsen postulated that the unique three-dimensional structure of a protein is determined by its amino acid sequence. This work laid the foundation for the sequence-structure-function paradigm, which states that the sequence of a protein determines its structure, and structure determines function. However, a class of polypeptide segments called intrinsically disordered regions does not conform to this postulate. In this review, I will first describe established and emerging ideas about how disordered regions contribute to protein function. I will then discuss molecular principles by which regulatory mechanisms, such as alternative splicing and asymmetric localization of transcripts that encode disordered regions, can increase the functional versatility of proteins. Finally, I will discuss how disordered regions contribute to human disease and the emergence of cellular complexity during organismal evolution.

Keywords: RNA localization; alternative splicing; biological networks; gene expression and regulation; intrinsically disordered proteins; protein turnover.

Figure 1.. Sequence to function relationship.

(A) Structure–function paradigm and (B) disorder–function paradigm. Reprinted with permission from ref. [7].

Figure 2.. The relationship between sequence composition and conformations adopted by IDRs.

(A) Plot of mean net charge versus mean hydrophobicity reveals the clear separation between structured proteins and IDPs. Reprinted with permission from ref. [31]. (B) Phase diagram showing the conformations of IDRs for different fractions of positive (f+) and negative charges (f−). Reprinted with permission from ref. [38]. FCR, fraction of charged residues; NCPR, Net charge per residue. (C) IDRs with sufficient hydrophobicity tend to fold upon binding (yellow, ACTR). Reprinted with permission from ref. [157]. ACTR, activator for thyroid hormones and retinoid receptors; ProTα-C, prothymosin α C-terminal segment; ProTα-WT, prothymosin α wild type; ProTα-N: prothymosin α N-terminal segment; IN, HIV integrase. (D) For the same net charge, the patterning can determine if the IDR adopts an extended coil or a collapsed globule conformation. Reprinted with permission from ref. [40].

Figure 3.. Advantages and functions mediated by IDRs.

(A) IDRs can link structured domains, where their flexibility permits the protein to adopt multiple conformations; linear motifs within IDRs mediate protein interactions; posttranslational modification of residues within IDRs permits encoding and decoding of information [106]. (B) IDRs in protein sequences can increase the efficiency of degradation by the proteasome, thereby regulating protein half-life [53].

Figure 4.. Coupled folding and binding of IDRs.

(A) p27–cyclin–CDK complex. Reprinted with permission from ref. [158]. (B) CBP–CREB interaction regulated by phosphorylation. Reprinted with permission from ref. [32]. (C) PUMA–MCL1 interaction in apoptosis. Reprinted with permission from ref. [159].

Figure 5.. Formation of nonmembrane-bound organelles and higher-order assemblies by IDRs.

(A) Self-association. Q/N-rich regions are important for P-bodies. Reprinted with permission from ref. [160]. FG-rich regions form hydrogel-like structures at the nuclear pore. Reprinted with permission from ref. [100]. (B) Multivalent interactions. Contacts between proteins containing repeating domains and peptide motifs can mediate phase transition that can be regulated via posttranslational modification. Reprinted with permission from ref. [92].

Figure 6.. TS splicing can rewire protein interaction and signaling networks.

TS splicing of IDRs can (A) affect interactions with other proteins by differential inclusion of linear peptide motifs and (B) influence whether a signaling enzyme can regulate a protein by differential inclusion of IDRs that contain posttranslational modification sites. Reprinted with permission from ref. [107].

Figure 7.. Impact of TS splicing of IDRs on protein networks and complexes.

(A) Rewiring of protein interaction networks and signaling pathways by TS splicing. Reprinted with permission from ref. [107]. (B) Expression of multiple isoforms can affect response kinetics and influence cellular decision-making (ultra-sensitive behavior, dominant-negative response, and sequestration of interacting partners, leading to gain or loss of function).

Figure 8.. Asymmetric localization of proteins with IDRs.

(A) Mechanisms to achieve asymmetric protein localization — transported after synthesis (TAS) or on-site synthesis (OSS) after asymmetric mRNA localization. (B) Advantages and implications of localized translation upon asymmetric mRNA localization. Reprinted with permission from ref. [108].

Figure 9.. IDRs and disease.

(A) IDRs are found in plaques and cellular deposits of patients with neurodegenerative disease. Reprinted with permission from ref. [161]. (B) Protein availability–outcome landscape. Tight regulation of proteins with IDRs (black arrow) ensures that they are present in the right amount and not longer than required. Adapted and reprinted with permission from refs [24,27,108].

Figure 10.. IDRs are fundamental units of protein function, regulation and evolution.

(A) Synergy between structured domains and IDRs increases the functional versatility of proteins. Reprinted with permission from ref. [12]. (B) Classification of IDRs and IDPs. Reprinted with permission from ref. [7].