Umeå University (UmU)

Postdoctoral Program in Integrated Structural Biology at Umeå University

Umeå University (UmU)

Umeå, Sweden

Up to 2 postdoctoral fellowships are open for the 2021 call at the Integrated Structural Biology (ISB) environment at Umeå University. Umeå University offers a vibrant and international atmosphere for structural biology research. There are 20 research groups and just above 100 persons affiliated with ISB. The ISB environment has regular seminars and candidates will be broadly exposed to different structural biology techniques. The university has state of the art infrastructure for cryoEM, NMR spectroscopy, supercomputing and x-ray crystallography (please visit https://www.biostruct.umu.se/ for details on research groups and equipment).

The openings will be filled using a procedure adapted from EMBL and top candidates that has applied to one of the 3 available projects will be selected. The projects are interdisciplinary and will ensure that the candidate will receive competitive training.

The program is open to all nationalities with relevant doctoral level education and work experiences and the openings will include the following to be considered by potential candidates:

  • Two years postdoctoral fellowship (incl. running costs) for research within a multidisciplinary structural biology environment.
  • Access to ISB affiliated core facilities and technical platforms.
  • Possibility for integration with the Umeå postdoc society (https://umeapostdocsociety.se/) for carrier development and joint activities.

Instructions

Candidates should submit their:

  • CV
  • Publications
  • Certificates and diplomas
  • A Motivation Letter (max 2 A4 pages), specifying: i) why you are interested in performing postdoc research studies within ISB and ii) why in particular you wish to do this with the PI:s and project idea selected from our list.
  • Research plan for the project (max 1 A4 page). We strongly encourage the applicants to contact the PIs for discussion of the project before submission.

Please email your application to ISB@umu.se no later than October 31. For inquires please contact the indicated lead-PI or co-PIs from the list of projects. Further info about the ISB Postdoctoral program can be found here: https://www.biostruct.umu.se/isb-postdoctoral-program/.

PROJECTS

Please find here below a list of the available projects together with contact information to PIs.

1. Structure of the membrane associated multimolecular complexes that make up the caveolae coat

Caveolae are small invaginations of the plasma membrane involved in regulating lipid homeostasis. Patients and mice models lacking key structural components of caveolae are severely impaired in their ability to store fat. Caveolae are formed by lipid-driven assembly of a multimolecular protein coat and stabilized at the plasma membrane via assembly of specific proteins around the caveolae neck creating a narrow membrane funnel. It is currently unclear how these proteins structurally assemble at the membrane interphase to sculpt the membrane into caveolae and restrain their scission from the plasma membrane. The idea of this project is to: a) Resolve the structure of the membrane associated caveolae coat proteins using purified components and lipid model systems and cryo-electron tomography and single particle analysis; b) structurally characterize the stabilizing protein-complexes at the caveolae neck using correlative light and electron microscopy (CLEM) volume imaging.

Lead PI: Linda Sandblad: linda.sandblad@umu.se

Co-PI: Richard Lundmark: richard.lundmark@umu.se

2. The molecular basis of neuronal death in ALS by SOD1 induced inhibition of cell-protecting human Bcl-2 protein.

In amyotrophic lateral sclerosis (ALS), mutations in superoxide dismutase (SOD1) promote disordered and misfolded conformers with a toxic gain of function, particularly in motor neurons. We aim to understand the structural basis for this neurotoxicity, which acts via mitochondrial dysfunction. It has been suggested that SOD1 proteins inhibit the cell-protecting (anti-apoptotic) Bcl-2 mitochondrial membrane protein. However, any molecular models are lacking. We assume that SOD1 interference with Bcl-2 will release its counterparts such as the apoptotic Bax, which will permeabilize mitochondrial membranes and induce cell death. Since Bcl-2 family members are also important regulators of mitochondrial metabolism, this basic mechanism might also contribute to a metabolic shift described in ALS patients and can be measured in ALS patient-derived cell models and would contribute to increased neuronal stress and ultimately, cell death.

Together with JG we could show by NMR that disordered apo-SOD1, but not normally folded holo-SOD1, can directly bind to full-length human Bcl-2 membrane protein, supporting a direct involvement of Bcl-2-inhibition in ALS. The interaction between apo-SOD1 and Bcl-2 was enhanced for a mutant (SOD1G93A) associated with an aggressive course of ALS, than for the wild-type protein. In this project, the postdoc will use NMR in complement with ITC to characterize Bcl-2 binding behaviour and affinities of various ALS-associated SOD1 mutants with different patterns of disease progression. Since our preliminary findings suggested that Bcl-2 undergoes conformational changes upon SOD1 binding, we will exploit by NMR (and Cryo-EM trials) the main structural rearrangements in Bcl-2/SOD1 upon association and their toxic consequences using cellular assays (JG). We will titrate the expression level of SOD1 isoforms in cell lines expressing different levels of Bcl-2, and correlate SOD1 expression and Bcl-2 interaction with endpoints including mitochondria function (Seahorse, mitochondrial membrane potential) cell viability (MTT reduction assay), apoptosis (Caspase activation) etc. In cell-based assays, Bcl-2 levels and SOD1 (mutant) expression levels can be modulated to understand downstream consequences of those interactions and subsequent metabolic shifts at organism level. This will provide a robust platform in which findings from NMR and ITC can be rapidly tested in a cellular model. This project will tackle Bcl-2 involvement in ALS and open up the way for therapies to fight ALS.

Lead PI: Gerhard Gröbner: Gerhard.grobner@chem.umu.se

Co-PI: Jonathan Gilthorpe: jonathan.gilthorpe@umu.se

3. Visualizing structure and dynamics of the anti-apoptotic Bcl-2 protein in its mitochondrial membrane environment.

The Bcl-2 (B-cell lymphoma 2) protein family regulates cell life and death in the intrinsic pathway of apoptosis by controlling permeability of the mitochondrial outer membrane (MOM), and plays a role in many forms of cancer and their treatment resistance. The molecular basis of how the Bcl-2 protein induces anti-apoptotic cell protection remains elusive due to a lack of structural information. To provide atomic-level dynamic structural insight into its functioning, we will exploit NMR and neutron reflectometry (NR) data (GG) to drive computer simulations (MA). Such data-driven approaches have emerged as a powerful tool with huge potential to extract detailed structural information from low-resolution data due to ever-increasing capabilities in parallel supercomputing and novel algorithms. The main aim of this postdoc project is to develop a data-driven simulation method to elucidate the structural basis of how the Bcl-2 protein interacts with the apoptotic (cell-killing) Bax protein to inhibit MOM damage and finally cell death.

The postdoc will be located and supervised by MA and will build simulation systems to extract structural information from NMR and NR data on the Bcl-2 and Bax proteins in mitochondria- mimicking bilayers. A computationally efficient way to generate in-simulation calculated scattering profiles will be developed to bias simulations towards a molecular-level structural solution. NMR and NR data will be provided by GG with a robust set of data already available. The project will generate new insight into a key step in mitochondrial apoptosis and it will put forward a data-driven approach that goes beyond today’s state-of-the-art to model neutron reflectometry data; which will be required at the upcoming national ESS infrastructure with its innovative reflectometry capabilities.

Lead PI: Magnus Andersson: magnus.p.andersson@umu.se

Co-PI: Gerhard Gröbner: Gerhard.grobner@chem.umu.se

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Position

Postdoctoral Program in Integrated Structural Biology at Umeå University