Intrinsically disordered proteins (IDPs) are highly abundant in the human proteome and mediate critical regulatory functions in the cell. The lack of stable globular structure confers numerous functional advantages on IDPs, allowing them to exert an exquisite level of control over cellular signaling processes. To perform their cellular functions, IDPs must frequently compete for binding to shared interaction hubs. The negative feedback regulator CITED2 efficiently downregulates the hypoxic response by displacing, in a unidirectional, switch-like manner, the hypoxia inducible transcription factor HIF-1α from the TAZ1 domain of the transcriptional coactivators CBP and p300. Displacement occurs by a facilitated dissociation mechanism involving a transient ternary intermediate formed by binding of the intrinsically disordered CITED2 activation domain to the TAZ1:HIF-1α complex. X-ray crystallographic and NMR studies reveal TAZ1-mediated negative cooperativity that results in nearly mutually exclusive binding of specific CITED2 and HIF-1α interaction motifs. Efficient competition for binding of the TAZ1 domain is dependent on the flexibility and multivalency of the HIF-1a and CITED2 activation domains. Differences in the strength of coupling of CITED2 and HIF-1a binding motifs are key determinants of unidirectionality and underscore the role of multivalency in regulation of cellular processes by IDPs.

Molecular mechanism of a unidirectional protein switch

ACS Spring 2022

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