m.wouters@victorchang.unsw.edu.au

Victor Chang Cardiac Research Institute

Structural bioinformatics

Proteins are essentially small machines. Understanding how they work is a challenge for structural biologists and structural data mining is a valuable tool in this quest. Protein conformational changes; their role in protein function; and the effect of mutations on protein function can all be studied using structural data mining.

A project to be selected from the following is available to a student with some training in bioinformatics and programming who is comfortable in a Unix-based environment.

Project 1:  Computational Analysis of human genetic disorders

Recent advances in high-throughput experimentation have shifted the emphasis of biological research from single molecules to whole systems. The partial map of the human interactome has permitted a genome-scale perspective of disease. This project will involve the development of computational methods to identify disease causing systems using comparative sequence analysis and protein-protein interaction data.

Selected References (Available on request)

• George RA, Liu JY, Feng LL, Bryson-Richardson RJ, Fatkin D and Wouters MA (2006) Analysis of protein sequence and interaction data for candidate disease gene prediction. Submitted

• Tiffin N, Adie E, Turner F, Brunner HG, van Driel MA et al. (2006) Computational disease gene identification: a concert of methods prioritizes type 2 diabetes and obesity candidate genes. Nucleic Acids Res. 34:3067-81.

• Franke L, Bakel H, Fokkens L, de Jong ED, Egmont-Petersen M, Wijmenga C. (2006) Reconstruction of a functional human gene network, with an application for prioritizing positional candidate genes. Am J Hum Genet. 78:1011-25.

• http://www.pathologene.org

Project 2:  EGF mutations associated with disease

Mutations in EGF domains are associated with a number of disease phenotypes including Marfan syndrome, Alagille syndrome, spondylocostal dysostosis and various blood diseases. The project aims to use structure and sequence analysis to investigate trends in the nature of mutations associated with disease. A benchwork component is available if desired.

Offered in conjunction with Dr Duncan Sparrow and Associate Professor Sally Dunwoodie

Selected Reference (Available on request)

• Wouters MA, Rigoutsos I, Chu CK, Feng LL, Sparrow DB, Dunwoodie SL. Evolution of distinct EGF domains with specific functions. Protein Sci. 2005;14:1091-103.

Project 3:  Exploring the genotype/phenotype relationships in lamin A/C

Mutations found in the LMNA gene that encodes the nuclear intermediate filament protein lamin A/C are associated with a variety of diseases including Emery-Dreifuss muscular dystrophy (EDMD), dilated cardiomyopathy (DCM), Dunnigan-type partial lipodystrophy, and Hutchinson-Gilford progeria. However, no simple relationship between the nature of these mutations and the tissue-specific phenotypes is immediately apparent. In this study, deletions and point mutants of the LMNA gene will be studied using molecular modelling and bioinformatics sequence analysis to explore the relationship between genotype and phenotype. A benchwork component is available if desired.

Offered in conjunction with Associate Professor Diane Fatkin

Project 4:  Evolution of transglutaminases from papain-like cysteine proteases

Transglutaminases are eukaryotic enzymes catalysing a variety of post-translational protein modifications including cross-linking of lysine and glutamine residues. Cross-links confer extra structural rigidity as well as resistance to proteolysis and are an essential component of important biological processes such as blood coagulation, hardening of the fertilization envelope and extracellular matrix assembly. Interestingly, these anabolic enzymes are thought to be descended from degradative enzymes, the papain-like cysteine proteases, based on similarities in structure and catalytic residues. In this study, structure/function changes in transglutaminases and related proteins will be investigated using structural comparison and phylogenetic techniques. A benchwork component is available if desired.

Offered in conjuction with Dr Siiri Iismaa and Professor Bob Graham

Selected References (Available on request)

• Wouters MA, Husain A. Changes in zinc ligation promote remodeling of the active site in the zinc hydrolase superfamily. J Mol Biol. 2001;314:1191-207.

• Iismaa SE, Holman S, Wouters MA, Lorand L, Graham RM, Husain A. Evolutionary specialization of a tryptophan indole group for transition-state stabilization by eukaryotic transglutaminases. Proc Natl Acad Sci U S A. 2003 100:12636-41.