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Protein-protein interactions in the control of eukaryotic gene expression

Jacqui Matthews and Joel Mackay with Merlin Crossley and Gerd Blobel (Children's Hospital of Philadelphia)

The expression of every gene in the genome of every organism is regulated at a number of levels, including transcription and RNA processing. Specific protein-protein, protei-RNA and protein-DNA interactions play a major role in this process and many disease states arise from problems with such interactions.

We are interested in understanding how protein interactions take place at a molecular level. In particular, given that many transcription factors appear to interact with multiple partners, we would like to understand how these different interactions synergise with or antagonize each other to achieve transcriptional control.

In order to do this, we have identified a number of protein domains that participate in specific interactions and are using a range of molecular biological, biochemical and biophysical methods to characterize these domains and the interactions in which they participate. We hope that the results of these endeavours will begin to provide a molecular framework that describes how proteins involved in regulating a process such as blood cell development cooperate to bring about the expression of the appropriate genes.

Protein design on a zinc-finger scaffold

Joel Mackay with David Segal (UC Davis)

Antibodies are extremely powerful molecular scaffolds because of their ability to specifically recognize a vast array of targets while retaining the same three-dimensional shape. This property (among others) has led to the development of a rapidly increasing number of antibody-based drugs. However, because of their large size and their requirement for disulphide bonds, they are less well-suited for intracellular targets.

We are seeking to develop zinc-binding domains as robust molecular scaffolds that can be adapted to target a wide range of intracellular proteins. Because of their small size (<~60 amino acids), lack of disulphides and robustness, they may be well-suited to this task.

To this end, we are currently exploring the tolerence of a number of zinc-binding folds to multiple (surface) mutations, and attempting to engineer novel binding functions onto existing domains using a combination of combinatorial (e.g., phage display) and rational design methods.

LIM-only proteins in blood development: characterization and drug design

Jacqui Matthews with Jane Visvader (WEHI)

LIM domains are zinc-binding modules that are found in many proteins, including a number of transcription factors. Proteins such as LMO2 and LMO4 (LIM-only 2 and 4) consist almost entirely of two LIM domains.

These proteins are involved in regulating the development of various cell types. Inappropriate expression of LMO2 in T-cells is linked with the development of T-cell leukemias, while LMO4 has been implicated in breast cancer.

Given that LIM domains are thought to be protein-protein interaction motifs, we believe that LMO proteins act as bridges, bringing together a number of other proteins (including ldb1, Tal, and the breast cancer related protein BRCA1) to form regulatory complexes.

We are using a range of biophysical, molecular biological and biochemical approaches to characterize these complexes. We hope to use this information to design specific molecules to inhibit the abherrent activity of these proteins.

EAS, a hydrophobic rodlet protein from Neurospora crassa

Ann Kwan with Margie Sunde (Pharmacology, USyd)

Regular arrays of small fibres or rodlets are a common feature of many dry-spored fungi. These water-repellent structures prevent wetting of the spores, thus allowing aerial distribution to occur. Recently, a gene involved in conferring hydrophobicity to aerial hyphae of Schizophyllum commune was identified and the term hydrophobin was coined for the class of small, cysteine-rich proteins which confer such proterties to aerial fungal structures. These proteins are potentially of substantial commercial interest, due to their ability to form polymeric monolayers on both biological and non-biological surfaces, and in doing so to transform the physical properties of these surfaces (from hydrophobic to hydrophilic and vice versa).

Dr Templeton has isolated and purified the protein comprising the rodlet layer of N. crassa (EAS, MW 7.9 kDa, eight Cys residues), and we have used NMR methods to determine the structure of this protein in solution. We are currently using a range of biophysical, biochemical and protein engineering methods to investigate the molecular basis for the formation of the EAS monolayers.


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