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Laboratory of Protein and DNA Interactions

All living organisms must be able to control expression of their genes with great precision. Within

cells, proteins known as transcription factors interact with DNA to control the on-off switches that

are found in the regulatory regions of genes. The interaction between these proteins and their

specific DNA binding sites is crucial for the correct temporal and spacial control of gene expression

networks.

We and others have shown that, in addition to functioning in dimerization, the PAS domains of

bHLH.PAS proteins have a critical influence on DNA binding, contributing to affinity and protein-

bound DNA conformation, as well as defining partner choice and target gene specificity.

� The molecular mechanisms that drive these functions of the PAS domain are not

known. In fact, although aspects of bHLH.PAS biology are the subject of much

research, few of the molecular events underlying gene regulation by these essential

proteins are understood.

The bHLH.PAS transcription factors are often coexpressed and their dimerisation behaviour is tightly

The basic Helix-Loop-Helix (bHLH) domain defines an

extensive transcription factor family. This domain consists of a

basic DNA binding sequence adjacent to the helix-loop-helix

dimerisation region, which allows homo- or hetero-dimerisation

amongst bHLH proteins to form functional DNA binding

complexes.

The bHLH.PAS sub-group of bHLH proteins has the bHLH

domain contiguous with a second domain, termed the

PAS (Per-Arnt-Sim homology) domain, which also

regulates dimerisation.

PAS domains are a widespread protein/protein interaction

module forming a highly conserved structure, despite

having low sequence homology. PAS protein interactions

are often regulated in response to signals detected by

the PAS domain, where PAS-bound small molecules

produce conformational changes that regulate activity,

and subtle conformational changes have large biological

consequences.

Page 1 of 2The University of Adelaide | Laboratory of Protein and DNA Interactions

17/07/2012http://www.adelaide.edu.au/mbs/research/dna/?template=print

regulated. The various protein dimers in the family bind to closely related DNA sequences, yet are

functionally distinct, being able to activate specific and discrete sets of target genes.

� The focus of our research is to understand the specificity of the bHLH.PAS

transcription factors, that is, to decipher the amino acids and structural elements of

the bHLH and PAS domains that control their protein-protein and protein-DNA

interactions.

The bHLH.PAS proteins we study have significant functions in biology:

Aryl hydrocarbon Receptor (AhR) mediates the severe toxicity associated with the

environmental pollutants dioxin, benzopyrenes, and structurally related halogenated aromatic

hydrocarbons.

Hypoxia Inducible Factors, HIF-1α and HIF-2α direct genomic responses to oxygen deficiency by

controlling genes that increase oxygen supply to tissues and facilitate metabolic adaption to

hypoxia. The HIFαs are important in anoxic human disease states, such as ischaemia and

myocardial infarction, and in cancer, where cellular responses to reduced oxygen are a crucial

component of tumour progression.

Single Minded proteins, Sim1 and Sim2 are involved in control of neural development and, like

the HIFαs, are both biologically essential and non-redundant.

Neural specific NPAS4, a stress induced bHLH.PAS transcription factor, has been found to be

active in rodents during chemically initiated epileptic seizure and may have a role in autism.

These bHLH.PAS proteins must dimerize with the common partner Aryl hydrocarbon Receptor

Nuclear Translocator (Arnt) for transcriptional function.

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Page 2 of 2The University of Adelaide | Laboratory of Protein and DNA Interactions

17/07/2012http://www.adelaide.edu.au/mbs/research/dna/?template=print