Researchers crack structures of human protein family
23 January 2009
In the study, Dr Alastair Barr and colleagues determined the high-resolution crystal structures of 22 human protein tyrosine phosphatases (PTPs), including 16 previously unpublished, with a detailed look at their biochemical properties.
PTPs are widely involved in cell signalling and play a key role in regulating cell functions and physiological processes, particularly in the immune system. There are 107 PTPs encoded in the human genome.
Previous Trust-funded studies have linked PTPs to type 2 diabetes. Genome-wide association studies conducted by the Wellcome Trust Case Control Consortium also linked PTPs with an increased risk of developing autoimmune diseases such as rheumatoid arthritis. The Consortium identified PTPN2 as increasing susceptibility to both type 1 diabetes and Crohn's disease - the first gene found that links these two diseases. Another gene, PTPN22, increases the risk of developing type 1 diabetes but seems to offer protection from Crohn's.
Other PTPs have been identified as tumour suppressor genes, the mutation of which can lead to the development of colorectal cancer.
"Due to their central role in most cellular processes it is no surprise that dysfunction of PTPs has been associated with a multitude of diseases and many members of the PTP family have now been recognised as potential therapeutic targets", said Professor Stefan Knapp, a co-author on the study.
"The large amount of structural and biochemical data generated from our study enabled us to compare this large human protein family on the molecular level. Our detailed comparison identified a number of structural features that can now be targeted for the design of selective PTP inhibitors."
Image: Molecular surface phosphatases coloured according to their charge properties; Wen Hwa Lee
References
Barr A J et al. Large-scale structural analysis of the classical human protein tyrosine phosphatome. Cell 2009;136:352-363.
Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Wellcome Trust Case Control Consortium. Nature 2007;447(7145):661-678.