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Proposing Institution

Lehrstuhl für Chemie der Biopolymere,TUM
Project Manager

Dr. Christina Scharnagl
Maximus-von-Imhof-Forum 4
85354 Freising
Abstract
Proteins perform countless functions thus enabling living cells to maintain their metabolism, to grow, to communicate with other cells etc. About 25% of all proteins in any organism are embedded within lipid membranes which define and structure individual cells and are built from a great variety of different lipid molecules. Most membrane proteins are anchored by helical transmembrane domains (TMDs) that are increasingly recognized to guide assembly of subunits to larger functional complexes and to have important impacts on the functional properties of the membrane. Previously, we have designed a large set of low-complexity model TMDs de novo and modeled their dynamics in isotropic solvent. Interestingly, the results show that the structural fluctuations along the helix strongly depend on their sequences which demonstrates that helix dynamics can be optimized by successive mutations in evolution and thus support the functional diversification of membrane proteins. Here, we plan to continue our analyses of how TMDs can affect the structure of the surrounding membrane and vice versa. Using established and novel LV-peptides, as well as natural TMDs, we thus mainly aim at uncovering i) the nature of molecular interactions between protein and lipid residues and ii) the impact of TMD dynamics on the long-range order of the membrane, i.e., on the way lipids are organized.Changes in membrane order underly complex biological processes, such as membrane fusion and lipid exchange. This work is thus expected to shed light on the mechanisms by which membrane proteins catalyze these functions. Another major project focuses on the role of helix dynamics and helix-helix recognition in Alzheimer’s disease. Alzheimer’s disease affects currently ~40 million people on earth and is expected to increase dramatically as a result of increasing life-spans. Although the etiology of the disease is still controversial, it is clear that cleavage of the Amyloid Precursor Protein (APP) TMD by gamma-secretase is an essential step leading to it. Successive cleavage leads to the build-up of Abeta peptides in the brain that ultimately kill nerve cells. The toxicity of these peptides depends on their size and size depends on the site of cleavage. Thus, understanding how individual cleavage events are influenced by the structure and dynamics of the APP TMD helix will provide a rationale for understanding a key step in this disease. So far, simulations of the APP TMD have mapped its site-specific backbone dynamics and thus complement corresponding experimental measurements. Our future studies aim at investigating the backbone dynamics of APP TMD mutants, that are known to cause early-onset Alzheimer by changing the cleavage pattern, and of non-APP substrates known to be cleaved with different efficiency. We thus want to clarify how regional changes in backbone dynamics change the effiency and specificity of the cleavage reactions. Further, we will investigate the interaction between the APP TMD helix and helices of presenilin, the enzymatic component of gamma-secretase, as well as its potential modulation by lipids to shed light on the hitherto poorly understood mechanism of substrate recognition by the enzyme.

Impressum, Conny Wendler