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Focused high throughput structure function analysis of human proteins involved into programmed cell death and inflammation


Programmed cell death and inflammation are two closely related, fundamental processes in eukaryotic cells. Defects in either process or in the signalling cascades leading to these processes have severe consequences including major diseases like cancer and au toimmune diseases. Here we want to investigate the biochemical and structural properties of human proteins involved in PCD and inflammation by state of the art high throughput means.

The key to any biochemical and structural analysis of a protein is the ability to express and purify the protein of interest. Methods adopted from structural genomics initiatives provide today the opportunity to investigate many constructs of proteins in parallel or entire protein families in a high throughput manner. As investigated system we have chosen the RIP kinase family and complexes, in which RIP kinases play a role. Recent results show that the RIP kinase are involved in key steps in PCD and inflammation and are therefore important regulatory proteins. They seem to have also higher affinities to several important small molecule kinase inhibitors, than the actual targets, e.g. Abelson or p38 kinase.

RIP kinases are known to form complexes using their N- or C-terminal protein-protein interaction domains to target the ki nase domains to their site of action. Furthermore, the heat shock protein 90 (HSP90) is believed to interact with the kinase domain of the RIP kinase family, similar to the cyclin in the cyclin dependent kinase super-family. Other targets enclose members of the Caterpiller superfamily of proteins. The Caterpiller proteins are multi-domain proteins with a highly homologous molecular architecture, comprising an N-terminal protein-protein interaction, followed by a NTP dependent oligomerisation domain, a C-term inal detection domain but are not well characterized. These multiprotein complexes serve as platform to activate e.g. RIP kinases or caspases, finally leading to cell death or inflammation.

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