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Structure and function of the SUMO specific protease SENP7

Reference	BB/F010125/1
Principal Investigator / Supervisor	Professor Ronald Hay
Co-Investigators / Co-Supervisors
Institution	University of Dundee
Department	College of Life Sciences
Funding type	Research
Value (£)	345,550
Status	Completed
Type	Research Grant
Start date	01/02/2008
End date	31/01/2011
Duration	36 months

Abstract

Proteases involved in processing ubiquitin and deconjugating ubiquitin from substrates are important components of the control mechanism that regulates the availability of 'ready to conjugate' ubiquitin and the modification status of individual proteins. Likewise, SUMO specific proteases are important determinants of SUMO modification status. Such enzymes are required for three distinct processes in SUMO metabolism. C-terminal hydrolase activity is used to process SUMO precursors to the mature forms. Once SUMO has been conjugated to substrate either as a single entity or as a polymeric chain SUMO specific isopeptidase activity is required for chain depolymerisation and deconjugation from substrates.While the SUMO specific protease SENP1, SENP2, SENP3, SENP5 and SENP6 have undergone some basic characterisation, the remaining protease, SENP7 is entirely uninvestigated. To establish the role of SENP7 in vivo we will use homologours recombination in chicken DT40 cells to 'knock out' the SENP7 gene. Phenotypic analysis of the cells should reveal the biological role of SENP7. In our preliminary experiments we have shown that SENP7 is unable to process SUMO precursors, has a very limited ability to deconjugate SUMO from a modified substrate, but efficiently depolymerises polySUMO-2 chains. As yet there are no structures and little understanding of how chains of ubiquitin or ubiquitin-like proteins are depolymerised. The previously determined structures of SENP1 and SENP2 bound to SUMO modified RanGAP1 indicated that the proteases made no contact with the RanGAP1 moiety. However the ability of SENP7 to cleave SUMO-2 dimers while being unable to remove a single SUMO from other substrates indicates that the protease is likely to make contacts with both SUMO moieties in the SUMO-2 dimers to stabilise a favourable cleavage conformation. A structure of such a complex would reveal important principles that hold for depolymerisation of all ubiquitin-like proteins.

Summary

We are what we are because of the genes we express. When translated into proteins these gene products have roles in catalysing chemical reactions, establishing the architecture of the cell and facilitating movement of materials within the cell. Simple nematode worms have about 13,000 genes, but although we humans are vastly more complex organisms we only have about twice the number of genes that the nematodes have. Clearly then the number of genes cannot explain our vastly increased complexity. However one way in which complexity can be increased is to link proteins together to generate new proteins. The ubiquitin like family of proteins can be covalently linked to a wide variety of proteins thus hugely increasing the complexity of our gene products. This has to be done under very well defined conditions where specific substrates are selected for modification by particular uibuqitin-like proteins. The importance of these pathways is manifest in the number of disease states that result when these processes fail or are carried out inaccurately. Modification status of any particular protein results from a delicate balance between conjugation and deconjugation. In the case of the Small Ubiquitin-like Modifier, SUMO, deconjugation is mediated by SUMO specific proteases The objective of the work proposed here is to understand how SUMO modified targets are selected for deconjugation by the SUMO specific protease SENP7. This particular enzyme has unique properties that could illustrate important principles in how ubiquitin-like proteins are deconjugated. The work will be carried out at the College of Life Sciences in the new James Black Centre at the University of Dundee and would involve collaborations with scientists at St Andrews University

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	Structural Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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