Structural characterization of mammalian bHLH-PAS transcription factors

Abstract

The mammalian basic helix-loop-helix-PER-ARNT-SIM (bHLH–PAS) transcription factors share common architectural features that include a bHLH DNA-binding domain and tandemly positioned PAS domains. The sixteen members of this family include the hypoxia-inducible factors (HIF-1α and HIF-2α), ARNT (also known as HIF-1β), CLOCK and BMAL1. Most bHLH-PAS proteins have been genetically linked to variety of diseases in humans, including cancers, metabolic syndromes and psychiatric conditions. To function as transcription factors, the bHLH-PAS proteins must form heterodimeric complexes. Recent crystallographic studies of HIF-α-ARNT and CLOCK-BMAL1 complexes have unveiled the organization of their multi-domain bHLH-PAS-A-PAS-B segments, revealing how these architectures can give rise to unique patterns of heterodimerization. As our structural understanding becomes better integrated with ligand-discovery and target gene identification, a more comprehensive picture of their architectural and functional properties will emerge.

Exploring the inhibition mechanism on HIF‐2 by inhibitor PT2399 and 0X3 using molecular dynamics simulations

“…Firstly, based on the average ΔG bind results of 3 apo systems, we can find that the value of binding free energy between HIF‐2α and ARNT for apo 2 (−25.09 ± 2.37 kcal/mol) is lower than that of apo 1 (−16.12 ± 2.89 kcal/mol) and apo 3 (−7.82 ± 1.19 kcal/mol), given that apo 2 is thermodynamically much more stable than apo 1 and apo 3. The result indicates that the second binding model from the PAS‐B domain of full‐length HIF‐2 may be dominate in solution, which is consistent with the viewpoints of Wu et al Compared with the respective apo system, the binding free energy between 2 monomers is reduced in the 3 PT2399‐bound systems (C1‐PT2399, C2‐PT2399, and C3‐PT2399). It means that the protein‐protein interactions of 3 models are disrupted as the binding of PT2399, which verifies the speculation from Rg analyses.…”

“…domain of full-length HIF-2 may be dominate in solution, which is consistent with the viewpoints of Wu et al17,50 Compared with the respective apo system, the binding free energy between 2 monomers is reduced in the 3 PT2399-bound systems (C1-PT2399, C2-PT2399, and C3-PT2399). It means that the protein-protein interactions of 3 models are disrupted as the binding of PT2399, which verifies the speculation from Rg analyses.…”

Transcriptional architecture of the mammalian circadian clock

“…Interestingly, a crystal structure of a another member of the bHLH-PAS heterodimeric protein family, HIF-2α-ARNT, reveals a completely different overall domain arrangement when compared to CLOCK:BMAL1, but specific domain interface interactions are preserved between the respective bHLH, PAS-A and PAS-B domains of the two subunits 164 (see REF. 165 for a comparison of these bHLH-PAS structures). The recognition of the CACGTG E-box DNA binding motif of the CLOCK:BMAL1 bHLH region is similar to that seen for other bHLH proteins 166 .…”

Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies

“…Our pan-cancer integrated analyses demonstrated that the circadian clock had both tumour-promoting and tumour-suppressing qualities that were cell-type dependent. Tumour hypoxia is linked to disease aggression and therapeutic resistance (22).Hypoxia inducible factors (HIFs), the master regulators of hypoxia signalling, are transcription factors containing PER-ARNT-SIM domains and are structurally analogous to core clock proteins BMAL1 and CLOCK (23)(24)(25), suggesting that both pathways can be co-regulated. Indeed, past reports have shown that hypoxic responses are gated by the circadian clock (26,27).…”