Invited Speaker

The Importance of the Calcium-Binding S100 Proteins and their Receptor RAGE in Clinical Diagnostics and as Drug Targets
Claus W.Heizmann
Switzerland

The rapid development of this topic is best illustrated when entering the word ‘calcium’ and ‘calcium diseases’ into the ‘Google’ database resulting in more than 20 and 10 millions entries, respectively. This reflects the plethora of vital physiological functions and metabolic processes regulated by calcium and the large number of human diseases linked to an altered calcium homeostasis. The calcium signal within cells is transmitted by the large family of calcium-binding proteins, characterized by a common structural element, the EF hand. The largest group within this family are the calcium regulatory S100 proteins with intra - as well as extracellular (cytokine-like) activities. Originally their name came from 2 proteins detected in 100% ammonium sulfate supernatant of a bovine brain extract; today more than 20 members are known to be expressed in a tissue and cell specific manner. These proteins have attracted great interest in recent years because of their close association with a number of human diseases and their use in clinical diagnosis. For example: S100B is a biomarker for brain damage in neurodegenerative and psychiatric disorders, S100A1 a putative marker for myocardial ischemia and S100A8/S100A9 and S100A12 are risk markers for inflammation and arthritis. Specific antibodies against S100A2 to S100A6 are useful for the immunhisto-chemical typing of tumors resulting in more subtle treatment of patients. Several S100 proteins, when secreted, interact with the Receptor for Advanced Glycation Endproducts (RAGE), a member of the immunoglobulin-like cell surface receptor subfamily also activated by amyloid beta and AGEs. Although RAGE expression is very low in most adult tissues, the specific accumulation of RAGE ligands, observed in a large number of pathological processes, results in the upregulation of RAGE.This leads to sustained activation and is the starting point of chronic cellular activation and tissue damage. It has been shown that secreted soluble RAGE (extracellular part of the receptor,composed of one V and 2- C-domains) binds to diverse RAGE ligands. Administration of sRAGE (or specific antibodies against the the individual sRAGE domains) is able to block/suppress Alzheimer’s disease-associated pathology, development of tumors and inflammation. We have investigated the structure and functions of this ligand-RAGE interactions, elucidated some signaling pathways and have identified the VC1 region site for therapeutic interaction which may lead to a better clinical management of human diseases.

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