DFG sponsored PHD position - Medizinische Hochschule Hannover

EXCELLENT MEDICINE IN HANNOVER
Hannover Medical School
Hannover Medical School – The Institute for Biophysical Chemistry – offers an
DFG sponsored PHD position
The research group headed by Prof. Dr. Dietmar Manstein has an open PhD position in the context of
the DFG-funded project “Allostery and Proteostasis of Regulated Actomyosin Systems in Human
Cardiomyocytes”.
FIELD OF WORK
Within the framework of this project, we aim to characterize the mechanochemistry, allostery, and
regulation of actomyosin complexes as they occur in human cardiomyocytes. The functional consequences of post-translational modifications, isoform-dependent differences, and disease-causing
mutations of myosin, actin, troponin, and tropomyosin are characterized with the help of actomyosin complexes that are reconstituted from correctly matched components. The selectivity and efficacy of small molecule-based approaches is evaluated in regard to changes in protein-protein interactions, allosteric communication, and protein stability. My team and I have shown that the small
molecule EMD 57033 can restore the activity to “dead” myosin protein that has been rendered inactive by stress-induced misfolding. Our work represents the first demonstration of a pharmacological chaperone-induced protein refolding, with subsequent restoration of the protein’s function.
Through a series of in vitro experiments, we have further shown that stabilization, refolding, and
increase of myosin force production can be mediated by other compounds and compound classes.
In the case of ß-cardiac myosin, we observed similar effects with thiadiazinone derivatives, small
metabolites, and peptides. We have started to combine the tools and methods developed in my
laboratory with sophisticated new instrument-based advanced to analyze the response of regulated
actomyosin complexes to different types of allosteric trigger events with sub-nanometer and submillisecond resolution. Therefore, we are now in a position to comprehensively investigate the
mechanisms underlying changes in motor activity or pharmacological chaperone-mediated protein
stabilization and refolding events. A better understanding of the underlying processes will aid in
the design and identification of compounds that act more selectively in regard to stabilization,
refolding, and activation of force production than EMD 57033. Higher affinity myosin effectors
with improved isoform-specificity are expected to foster the development of powerful new
therapeutic tools to treat genetic and non-genetic forms of striated muscle diseases including
heart failure. Better understanding and appreciation of their effects in regard to enzymatic turnover and proteostasis will help to improve the design of clinical studies and facilitate the interpretation of the clinical effects observed in trials. Moreover, we expect that the results obtained with
myosin can serve as a paradigm for the development of small molecule-based approaches to induce
the pharmacological chaperone-mediated refolding of other types of proteins, such as those
associated with the accumulation of misfolded protein in the central nervous system.
YOUR PROFILE
We are looking for talented individuals who are excited about research. You should hold a master’s
degree in biochemistry, biophysics or a related area with an excellent academic record. You will solve
high-resolution structures of regulated actomyosin complexes, elucidate their functional properties,
and generate accurate models of related interaction networks that govern the motile behavior of
cells. Previous experience in the purification and characterization of proteins and an affinity for exact
quantitative approaches are required. Fluency in spoken and written English is expected.
OUR OFFER
Hannover Medical School (MHH) and the Institute for Biophysical Chemistry are offering excellent
working conditions and a stimulating research environment. The DFG-funded position is available
from October 2016 onwards for a period of three years.
HOW TO APPLY
Please send your application by electronic mail and preferably in one single PDF document to
[email protected]. For full consideration, the application should include a cover
letter, a detailed CV, copies of all educational certificates and transcripts of records, a summary of
previous research, and two letters of recommendation. The deadline for application is November 30,
2016. Early applications are encouraged; applications may be processed as they are received. MHH is
an equal opportunity employer. Qualified women are therefore particularly encouraged to apply.
Applicants with disabilities are treated with preference given comparable qualification.
Medizinische Hochschule Hannover
Prof. Dr. Dietmar J. Manstein · Institut für Biophysikalische Chemie
Carl-Neuberg-Str. 1 · Gebäude J3 · Ebene 2 · Raum 1330 · D-30625 Hannover
T: +49-511-5323700 · Web: http://www.mh-hannover.de/bpc.html
RELATED REFERENCES
1. Behrmann, E., Müller, M., Penczek, P.A., Mannherz, H.G., Manstein, D.J., and Raunser, S. (2012).
Structure of the rigor actin-tropomyosin-myosin complex. Cell 150, 327-338.
2. Brandstaetter, H., Kishi-Itakura, C., Tumbarello, D.A., Manstein, D.J., and Buss, F. (2014). Loss of
functional MYO1C/myosin 1c, a motor protein involved in lipid raft trafficking, disrupts autophagosome-lysosome fusion. Autophagy 10, 2310-2323.
3. Hundt, N., Preller, M., Swolski, O., Ang, A.M., Mannherz, H.G., Manstein, D.J., and Müller, M.
(2014). Molecular mechanisms of disease-related human ß-actin mutations p.R183W and p.E364K.
Febs J, n/a-n/a.
4. Hundt, N., Steffen, W., Pathan-Chhatbar, S., Taft, M.H., and Manstein, D.J. (2016). Load-dependent
modulation of non-muscle myosin-2A function by tropomyosin 4.2. Sci Rep 6, 20554.
5. Manstein, D.J., and Mulvihill, D.P. (2016). Tropomyosin-mediated Regulation of Cytoplasmic Myosins.
Traffic.
6. Muennich, S., Taft, M.H., and Manstein, D.J. (2014). Crystal Structure of Human Myosin 1c-The
Motor in GLUT4 Exocytosis: Implications for Ca (2+) Regulation and 14-3-3 Binding. J Mol Biol 426,
2070-2081.
7. Preller, M., and Manstein, D.J. (2013). Myosin structure, allostery, and mechano-chemistry. Structure 21, 1911-1922.
8. Radke, M.B., Taft, M.H., Stapel, B., Hilfiker-Kleiner, D., Preller, M., and Manstein, D.J. (2014). Small
molecule-mediated refolding and activation of myosin motor function. Elife 3, e01603.
9. von der Ecken, J., Heissler, S.M., Pathan-Chhatbar, S., Manstein, D.J., and Raunser,
S. (2016). Cryo-EM structure of a human cytoplasmic actomyosin complex at
near-atomic resolution. Nature 534, 724-728.
10.von der Ecken, J., Müller, M., Lehman, W., Manstein, D.J., Penczek, P.A., and
Raunser, S. (2015). Structure of the F-actin-tropomyosin complex. Nature 519,
114-117.
www.mh-hannover.de

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