Structural determinants of Siah ubiquitin ligase complexes

Funded Activity Summary

Controlled degradation of cellular proteins is an important process. The turnover of proteins is a fine balance between protein expression and degradation and alterations can control many cellular processes such as mitosis and intracellular signaling. Whilst a lot of research has been directed at understanding protein expression in response to stimuli such as hormones, stress etc. little has been known about the mechanisms for targeting protein degradation. In recent years it has been shown that proteins can be modified by the addition of a signaling protein called ubiquitin, and it is this modified form that is recognised for degradation. The degradation of these proteins occurs within a large protein complex called the proteasome, which recognizes the ubiquitinated protein substrates. The ubiquitination of proteins is a multistep process, the final step of which is catalyzed by a ubiquitin ligase, or E3 enzyme. It is the E3 which is able to recognize the protein to be degraded, and catalyze the transfer of ubiquitin onto that protein. The E3 proteins (or sometimes complexes) are a diverse group which have to recognize many different proteins, in order that they be degraded at appropriate times. We have been working on the protein Siah (seven in absentia homologue), a member of an E3 complex and important in controlled cell death, cell division and inflammatory responses. One part of the Siah protein is involved in binding proteins and targeting them for ubiquitination, though it is not known how Siah recognizes its targets. Using protein crystallography we have solved the 3D structure of this part of Siah and now propose to co-crystallize Siah with target proteins and binding partners so as to understand how Siah recognizes these proteins. Understanding the basis of these interactions will allow us to determine other potential targets for the Siah protein and also how we may be able to interfere with these interactions with therapeutic drugs.

Funded Activity Details

Start Date: 01-01-2003

End Date: 01-01-2005

Funding Scheme: NHMRC Project Grants

Funding Amount: $267,750.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Biochemistry And Cell Biology Not Elsewhere Classified

ANZSRC Socio-Economic Objective (SEO)

There are no SEO codes available for this funding activity

Other Keywords

cancer | cell biology | crystallography | degradation of cellular proteins | neurological disorders | protein/protein interaction | ubiquitination of proteins

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