Fachbereich 5

Biologie


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SFB - Seminar 

»The pattern recognition receptor RAGE and its ligands«

23. Mai 2017 · 17:15 Uhr
Gebäude 35/E01
(Barbarastraße 11)

PD Dr. Günter Fritz, Universitätsklinikum Freiburg

 

The receptor for advanced glycation endproducts (RAGE) is a key molecule in the onset and sustainment of the inflammatory response. RAGE binds a large number of different ligands and is therefore considered as a pattern recognition receptor recognizing rather a structural motif than a specific ligand. Among the ligands are the so-called advanced glycation endproducts that occur in elevated levels in diabetes patients, amyloid , LPS, and danger associated molecular pattern molecules (DAMPs) like HMGB1 or members of the calgranulin/S100 protein family. The surface levels of RAGE are highly dynamic and are largely increased during inflammation; likewise, there is an upregulation of RAGE ligands. Recent structural information on the extracellular portion of RAGE and on different S100 proteins shed new light on this unusual receptor –ligand pair and put forward different models of receptor activation and regulation. X-ray crystallographic and biochemical data suggest that RAGE-ligand binding is largely driven by electrostatic interactions RAGE.

J. Piehler

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SFB - Seminar 

»Structural and functional analysis of the TSC complex to improve molecular diagnostics for tuberous sclerosis complex«

30. Mai 2017 · 17:15 Uhr
Gebäude 35/E01
(Barbarastraße 11)

Dr. Marc D. Nellist (Department of Clinical Genetics, Erasmus MC, Rotterdam, NL)

 

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by inactivating mutations in the TSC1 and TSC2 tumour suppressor genes. Individuals with TSC are characterised by a combination of neurological symptoms and the occurence of hamartomous lesions in many different tissues, notably the skin, kidneys and brain.
TSC1 and TSC2 encode major components of the TSC complex, a large oligo-heteromer that is a specific GTPase activating protein (GAP) for the RAS homolog enriched in brain (RHEB). The TSC complex dependent conversion of RHEB-GTP to RHEB-GDP inhibits the mechanistic target of rapamycin (mTOR) complex 1 (TORC1), a major regulator of anabolic metabolism, and loss of TSC complex function results in increased protein synthesis and cell growth.
Molecular genetic testing results in the identification of a pathogenic TSC1 or TSC2 mutation in most individuals with TSC. This helps establish a diagnosis and provides useful information for therapeutic and family planning purposes. In some cases, however, no pathogenic mutation is identified. These individuals are referred to as TSC 'no mutation identified' (NMI). In some TSC NMI individuals the pathogenic mutation may not be detectable using standard screening methods while, in other cases, variants of uncertain clinical significance (VUS) are identified. Sometimes these nucleotide changes are unlikely to prevent TSC1 or TSC2 expression, but could affect TSC complex function. We have used a combination of targeted Next Generation Sequencing (NGS) and functional assays to improve the identification and classification of TSC1 and TSC2 variants.
Using targeted NGS we have identified and validated the presence of a pathogenic variant in 45/77 TSC NMI cases (58%), increasing the diagnostic yield for the molecular screening of individuals with TSC.
To help classify TSC1 and TSC2 VUS, we have performed functional testing of >300 TSC1 and TSC2 variants. Our work has provided insight into the genetic risks in the families segregating the tested variants and into the structure and function of the TSC complex. Investigating the effects of VUS on TSC complex activity is a useful adjunct to standard genetic testing and has been implemented as a diagnostic test in our laboratory.
I will present a brief summary of the results of our NGS-based analysis, and an overview of our functional and structural studies on the TSC complex..

D. Kümmel

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