Cellular Responses

Disordered proteins make a dynamic switch

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Science  21 Apr 2017:
Vol. 356, Issue 6335, pp. 281-282
DOI: 10.1126/science.356.6335.281-e

The proteins that regulate cellular responses to hypoxia form a sensitive on-off switch. Cells survive hypoxia by activating the transcription factor HIF-1α (hypoxia-inducible factor 1α). HIF-1α is active when it is associated with the transcriptional coactivator CBP. The protein CITED2 opposes such activation. CITED2 and HIF-1α bind overlapping regions of CBP with similar affinity. But CITED2 can much more effectively displace HIF-1α from CBP and inhibit transcription. The flexibility of intrinsically disordered regions of CITED2 apparently allows it to slip in and cause an allosteric change in CBP that hinders interaction with HIF-1α. Other such switches may exist, and in such cases, modeling on the basis of binary dissociation constants would be very misleading.

Nature 10.1038/nature21705 (2017).

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