John Sheehan, PhD

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• Publication List

RESEARCH INTERESTS:

Understanding the Role of Glycoconjugates in Biology

The biology of carbohydrate-rich molecular assemblies is relatively little studied as compared with proteins and nucleic acids. However nearly all secreted proteins are glycosylated and biological surfaces  whether of single cells, tissues or whole animals are typically richly coated with a variety of large glycoconjugates including large molecules such as polysaccharides, proteoglycans and mucins. These substances provide the framework around which many structural and protective functions are based.

My biochemical work is centred upon the characterization of the large mucin gene products (Mr 2-3 million) and the complexes they make (Mr 10-100 million) essential for the formation of the mucus gels vital for epithelial protection and function. This work is focussed around the human lung where there are many human diseases including asthma, cystic fibrosis, and chronic bronchitis in which these glycoconjugates are centrally implicated. Our studies are broad ranging and seek to build up a picture of the chemistry of these complex phenotypes, the network of their interactions that constitutes a mucosal surface and the mechanisms of their biosynthesis, assembly and secretion.

Interest in carbohydrates leads one naturally to consider water and its central role in Biology. In my own work the study of the dynamics of carbohydrate-water interactions using computer based molecular dynamics simulations  has been very informative and illuminating in understanding biomolecule structure and function in general.   I have employed the polysaccharide, hyaluronan, a ubiquitous and vital molecule found in virtually all higher multicellular organisms, as a model system for testing structural and hydrodynamic predictions flowing from dynamic calculations.

The laboratory is established with a wide range of state of the art biochemical, chemical and physical methods including MALDI and ESI mass spectrometry, electron and atomic force microscopy, hydrodynamics, theoretical molecular dynamics and a variety of surface physics tools.

RECENT PUBLICATIONS:

Sheehan JK, Kesimer M, Pickles R. Innate immunity and mucus structure and function. Novartis Found Symp. 2006;279:155-66; discussion 167-9, 216-9

Scott PG, Dodd CM, Bergmann EM, Sheehan JK, Bishop PN. Crystal structure of the biglycan dimer and evidence that dimerization is essential for folding and stability of class I small leucine-rich repeat proteoglycans. J Biol Chem. 2006 May 12;281 (19):13324-32. Epub 2006

Thelin WR, Kesimer M, Tarran R, Kreda SM, Grubb BR, Sheehan JK, Stutts MJ, Milgram SL. The cystic fibrosis transmembrane conductance regulator is regulated by a direct interaction with the protein phosphatase 2A. J Biol Chem. 2005 Dec 16;280(50):41512-20. Epub 2005