Current Job Openings

We have currently two openings for a PhD student or Master thesis project:

Master thesis in structural biology of amyloids

Our group is looking for a biochemistry, biophysics or molecular biology master student to work on a project dedicated to the study of the impact of different nucleation pathways in amyloid fibril structure. 

Protein misfolding can lead to the appearance of ordered structures – amyloid fibril. The results of numerous studies have shown that a lot of (and possibly all) proteins are capable to form amyloid-like fibrils, so that, perhaps amyloid-like fibrils are one of the basic states of the protein. Currently, there are more than 40 proteins known to form amyloid fibrils, associated with various diseases. Aggregation of beta-amyloid peptides (Aβ) in the brain tissue is a biomarker of one of the most common neurodegenerative diseases – Alzheimer’s disease (AD). Amyloid fibrils exhibit a certain degree of polymorphism when prepared under different conditions. It is discussed that Aβ fibrils from different AD patients might even adopt different structures. Therefore, different Aβ fibril structures under various fibril preparation conditions and seeding can lead to different aggregation pathways and result in fibril polymorphism.

The project will include recombinant protein expression in E.Coli, purification  and protein characterization with SDS and native page, size exclusion chromatography, dynamic light scattering as well as solution state NMR, DLS and native page. Aggregation kinetics using Thioflavin T fluorescence assay and transmission electron microscopy should be studied and characterized using different models of fibrillation. MAS solid-state NMR spectra of the fibrils obtained under different conditions should be recorded for characterization of the changes in the structure of the mature fibrils. 

The proposed project consists of 70% wet lab work and 30% computer analysis. Our group has a very friendly working environment. The protein production and most of the experiments are well established in the lab. The proposed project should be doable in 6 months. Basic practical knowledge of molecular biology, biochemistry and biophysics methods as well as quantum physics would be an advantage. No experience in NMR is required. 

AA amyloidosis and serum amyloid A (SAA)

In collaboration with the group of Prof. Marcus Fändrich, Universität Ulm, we investigate aggregates formed by the protein SAA. AA amyloidosis is a protein misfolding disease that affects humans and animals (Westermark et al., 2015, Obici & Merlini, 2012). The disease accompanies chronic inflammatory conditions, such as rheumatoid arthritis, leprosy or tuberculosis. Its amyloid fibrils consist of AA protein, which represents mostly a 76 amino acid fragment from the N-terminus of SAA1 protein. SAA1 is an extracellular blood apolipoprotein that becomes strongly upregulated during inflammation.

It will be the goal of the study to obtain a structural model of a monomer in the SAA1 fibril based on solid-state NMR and to perform an integrated structural analysis using solid-state and cryo-EM data.

image: Lu et al. (2014) Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis. Proc. Natl Acad. Sci. U.S.A. 111: 5189-5194.

Binding of PET tracer molecules in neurodegenerative diseases

In collaboration with the groups of Prof. Hans-Jürgen Wester and Dr. Behrooz Yousefi at the TUM, we investigate how PET tracer molecules interact with Alzheimer's disease Aβ and Parkinsons's disease α-synuclein aggregates. PET tracer molecules are diagnostic markers that allow to recognize early-on a particular neurodegenerative disease. So far it is not easily possible to differentiate between different neurodegenerative diseases. Wester and Yousefi have now designed bithiazole derived small molecules that have strongly different binding properties to Aβ and α-synuclein, respectively (Yousefi et al., ACS Med. Chem. Lett. 2011; Yousefi et al., ACS Chem. Neuroscience 2015), that are employed for detection of amyloid deposits in vivo.

It will be the aim of the project to determine the atomic level structure of the small molecule - aggregate complex using MAS solid-state NMR, and to suggest small molecule derivatives with improved binding properties.

image: Dr. Behrooz Yousefi, Prof. Hans-Jürgen Wester, TUM