Functional advantages of dynamic protein disorder

Abstract

Intrinsically disordered proteins participate in many important cellular regulatory processes. The absence of a well-defined structure in the free state of a disordered domain, and even on occasion when it is bound to physiological partners, is fundamental to its function. Disordered domains are frequently the location of multiple sites for post-translational modification, the key element of metabolic control in the cell. When a disordered domain folds upon binding to a partner, the resulting complex buries a far greater surface area than in an interaction of comparably-sized folded proteins, thus maximizing specificity at modest protein size. Disorder also maintains accessibility of sites for post-translational modification. Because of their inherent plasticity, disordered domains frequently adopt entirely different structures when bound to different partners, increasing the repertoire of available interactions without the necessity for expression of many different proteins. This feature also adds to the faithfulness of cellular regulation, as the availability of a given disordered domain depends on competition between various partners relevant to different cellular processes.

Keywords: Coupled folding and binding; Post-translational modification; Transcriptional activation.

Figure 1

Motifs play a critical role in molecular recognition by p53. Structures of the p53 transactivation domain (blue) in complex with MDMX (left), replication protein A (middle), the NCBD domain of CBP (right) are shown to illustrate how p53 uses its different interaction motifs to bind to multiple proteins.

Figure 2

Schematic representation of proposed mechanisms for coupled folding and binding processes of IDPs. The induced folding mechanism suggests that initial binding events trigger the IDP to adopt its folded conformation in complex with its target, whereas the conformational selection mechanism requires some population of the free IDP to adopt its structured conformation in the unbound state. Examples from the literature support both of the proposed mechanisms.

Figure 3

The HIF-1α transactivation domain can adopt multiple structures. HIF-1α binds to the TAZ1 domain of CBP in a helical conformation (left; for clarity, only one of the three helices formed in HIF-1α is shown). The same region of HIF-1α binds to FIH in an extended conformation (right). Residues 795–805 of the HIF-1α C-terminal transactivation domain are shown in green. The sidechain of asparagine 803 is highlighted in orange.

Figure 4

Sequence of the amino-terminal transactivation domain of p53. Known phosphorylation sites are mapped onto the primary sequence of human p53 in red lettering. The locations of the amphipathic AD1 and AD2 binding motifs are shown below the sequence.