We are very happy that Jonas Barandun was awarded the ERC Starting Grant 2020! More info here.
A new article from the Berntsson lab, with Dr. Andreas Schmitt as lead author, has just been accepted in the Journal of Molecular Biology, see here for the full (curently pre-proof version) article.
A PhD position in biochemistry is available in the laboratory of Professor Magnus Wolf-Watz at the Department of Chemistry, Umeå University, Sweden. The PhD project is aimed at uncovering novel molecular mechanisms underlying the function of human protein kinases. Focus will be on two specific protein kinases that are intimately linked to a number of disorders in humans including various forms of cancer. The doctoral student will enter a multidisciplinary project that is built on collaborations with both Professor Kwangho Nam at University of Texas Arlington and with Marené Landström (Professor in pathology at Umeå University). The doctoral student will be trained in structural biology, protein production, biochemistry and biophysics and will collaborate with both cell biologists and computational chemists. Structural biology may go in any of the directions; single particle cryo EM, x-ray crystallography or protein NMR spectroscopy depending on the development of the research project and also depending on the interests of the doctoral student. The position is in part funded by the National Institute of Health (NIH).
Please contact firstname.lastname@example.org for more information
Click here for the on-line application https://umu.varbi.com/se/what:job/jobID:328538/
Up to 3 postdoctoral fellowships are open for the 2020 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 19 research groups and close to 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 www.biostruct.umu.se for details on research groups and equipment).
The openings will be filled using a procedure adapted from EMBL and up to 3 top candidates that has applied to one of the 7 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 funding (incl. running costs) for research within a multidisciplinary structural biology environment
- Access to ISB affiliated core facilities and technical platforms
- Integration with postdocs at ISB and also MIMS (Molecular Infection Medicine Sweden) for carrier development and joint activities
Candidates should submit their:
- 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.
- Reseach 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 April 13. For inquires please contact the indicated lead-PI or co-PI’s from the list of projects. Further info about the ISB Postdoctoral program can be found here: https://www.biostruct.umu.se/isb-postdoctoral-program/
Please find here below a list of the available projects together with contact information to PI’s.
Membrane interactions during apoptosis – a data-driven simulation approach
The grand challenge in low-resolution structural biology methodologies is the structural interpretation of the data. In recent years, data-driven computer simulation has 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 mechanism behind the association of apoptotic Bax protein to mitochondrial-membrane interfaces and its subsequent partitioning; information essential for a molecular understanding of a key step in apoptosis, namely the cell-death causing membrane perforation.
The work includes building of simulation systems to mimic the mitochondrial lipid composition under apoptotic oxidative stress conditions, hydration levels, and protein content, as used in the neutron reflectometry experiments. A computationally efficient way to generate in-simulation calculated scattering profiles will be developed to bias simulations towards a molecular-level structural solution; work to be supervised by Dr. Andersson. Importantly, the postdoc will be involved in sample preparation and all stages of the neutron scattering experiments, supervised by Dr. Gröbner (and preliminary data already at hand). 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: email@example.com
Co-PI: Gerhard Gröbner: firstname.lastname@example.org
Structural studies of virus-host interactions by cryo-electron tomography on virus-infected human organoids
What questions molecular biologists can answer is highly dependent on the research methods and model systems at their disposal. In this project we aim to combine cutting-edge advances in both infection models and cryo-electron tomography to study human enteric viruses. The group of Niklas Arnberg has long experience in working with both enteroviruses and with enteric adenoviruses. The Arnberg group are currently establishing human gut organoids (“enteroids”) as a more realistic model system to study infection of the gut. On the structural biology side, a major limitation for structural analysis by cryo-EM is the sample size. The standard plunge-freezing methods used in cryo-EM can only vitrify samples to a thickness of ~1 μm. Leveraging on the extensive infrastructure at UCEM, the Carlson group have developed a high-pressure freezing-based method that would allow structural studies by cryo-electron tomography of virus-infected organoids. Combining these methods, the postdoc will be able to study host-cell remodelling by enteric viruses in situ in human organoids. This will allow visualisation of complex tissue-dependent processes, e.g. depending cell type and tissue polarity, with the unprecedented structural fidelity of cryo-electron tomography.
Lead PI: Lars-Anders Carlson: email@example.com
Co-PI: Niklas Arnberg: firstname.lastname@example.org
Mechanistic study of the autophagic protein ATG8/LC3 in membrane morphogenesis using NMR
Autophagy is a highly conserved and sophisticated “self-eating” process in eukaryotes and plays a key role in human health and disease. Formation of double- membrane autophagosomes is the key process in autophagy. The LC3 protein family (mammalian homologs of yeast ATG8) conjugated to phosphatidylethanolamine (PE) is required for autophagosomal membrane expansion and closure. However, the molecular mechanisms of these processes remain unclear. We have earlier prepared LC3-PE proteins by semisynthetic approaches and showed that LC3-PE promotes membrane fusion in vitro. The aim of this project is to gain molecular insights into how ATG8/LC3-PE mediates membrane morphogenesis. To this end we will use structural biology tools, primarily NMR, to study ATG8/LC3-PE together with lipids. NMR can provide a wealth of information about not only protein structure, but also details about lipid properties in membrane bilayers. In this way we can simultaneously investigate the effect that lipids have on the properties ATG8/LC3-PE and the effect that the protein has on membrane morphology. The work will involve both protein chemistry, and advanced NMR spectroscopy to study both protein structure, and lipid properties.
Lead PI: Lena Mäler: email@example.com
Co-PI: Yaowen Wu: firstname.lastname@example.org
Understanding assembly and function of the bacterial cell wall
Bacteria are protected from environmental insults by a peptidoglycan (PG) cell wall. Hence, the enzymes involved in the production and turnover of PG are preferred targets for many of our most successful antibiotics. However, emerging resistant bacteria are threatening the very foundations of modern infection medicine by eroding the efficacy of our antibiotic arsenal. Identifying new genetic determinants of the bacterial cell wall as antibiotic targets, and characterizing them biochemically and structurally is of highest international priority but turns out to be a very difficult task. Our team has discovered a novel Penicillin Binding Protein conserved in a number of Gram-negative pathogens (e.g. Vibrionaceae, Pseudomonadaceae, Burkholderiaceae). Preliminary data shows that it supports PG fitness under challenging environmental adaptation (e.g. low osmolarity), suggesting that it could be a new phylum-specific antimicrobial target. This research is focused on characterizing structurally and biochemically this new PBP from V. cholerae – Vc1321. It’s is a membrane protein of 1023 amino acids. The protein is likely dimeric through disulfide bridges. We have demonstrated its bifunctional transglycosylase and transpeptidase domains both in vitro and in vivo and we are now applying all sorts of genetics to understand more about its biological function and network partners.
Vc1321, renamed as PBP1V, has been cloned, expressed and purified. Characterization of the structure, kinetics, and dynamics would help to understand catalytic peculiarities and putative interaction domains with other partners. Understanding the nature and function of PBP1V might provide a new way to increase our armory of growth-affecting compounds of low or no toxicity, an unexplored ground for the development of a species-specific class of antimicrobials for clinical therapies.
Lead PI: Elisabeth Sauer-Eriksson: email@example.com
Co-PI: Felipe Cava: firstname.lastname@example.org
Green Structural Biology in cellulose and silk biotechnology
An important aspect of green chemistry and a sustainable and circular economy is to develop environmentally friendly methodology to retrieve valuable chemicals from complex biomaterials. This interdisciplinary project tackles this challenging task by exploring the molecular mechanisms underlying enzymatic processing of recalcitrant natural polymers: cellulose and silk fibers. In the project we focus on two enzymes that bring novel functionality in cellulose and silk bio-processing by softening their structure and paving the way for further biocatalytic transformation of the fibers.
We are seeking a structural biologist with a strong background in biochemistry and/or protein production with different expression organisms. The structural biology background may be in any of the areas of NMR spectroscopy, single particle cryo EM or x-ray crystallography. The project is based on novel discoveries in both the Jönsson and Wolf-Watz laboratories. The successful candidate will have the possibility to define and shape the project dependent on background and ambitions and may focus on both enzymes and/or the structures of cellulose and silk-based biomaterials.
Lead PI: Magnus Wolfl-Watz: email@example.com
Co-PI: Leif Jönsson: firstname.lastname@example.org
Multimolecular complexes providing surface stability of caveolae and direct connection sites to the endoplasmatic reticulum for fatty acid uptake
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 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 of the caveolae neck to mediate stabilization of caveolae. Furthermore, based on preliminary data, we hypothesize that the role of caveolae in fatty acid uptake is conveyed by direct connection sites between caveolae and cellular organelles. The idea of this project is to; a) structurally characterize the stabilizing protein-complexes at the caveolae neck as well as connection sites to organelles in cells using correlative light and electron microscopy (CLEM) volume imaging. b) Resolve ATP-dependent kinetics and structural rearrangements in caveolae-stabilizing proteins during membrane assembly at high temporal resolution using reconstituted model systems.
Lead PI: Linda Sandblad: email@example.com
Co-PI: Richard Lundmark: firstname.lastname@example.org
Co-PI: Magnus Andersson: email@example.com
Structural basis of misfolded SOD1 toxicity in human motor neurons
ALS is a rapidly progressing neurodegenerative disease with no cure. Protein unfolding, misfolding and aggregation are intimately linked to the etiology of the ALS and seem to involve prion-like mechanisms of templated protein aggregation. However, the structure of misfolded protein species responsible for ALS has yet to be defined. The gene encoding the SOD1 protein was the first identified genetic cause of ALS and we have now identified a highly cytotoxic form of the misfolded SOD1 protein derived under defined conditions in vitro. The aim of this project is to resolve the structure this potentially disease-causing form of SOD1 using Cryo-EM, and also study its localization and protein interaction in cultured human patient derived motor neurons using correlated light and electron microscopy (CLEM) including tomography. This will enable the structure and activity of SOD1 protein aggregates to be understood in relation to ALS.
Lead PI: Linda Sandblad: firstname.lastname@example.org
Co-PI: Jonathan Gilthorpe: email@example.com
Co-PI: Richard Lundmark: firstname.lastname@example.org
Martínez-Carranza M, Blasco P, Gustafsson R, Dong M, Berntsson RP, Widmalm G, Stenmark P. Synaptotagmin Binding to Botulinum Neurotoxins. Biochemistry in press. doi: 10.1021/acs.biochem.9b00554
In an article in the latest issue of “Kemisk Tidskrift” Jonas Baranduns “tiny” ribosome structure is shown together with an update on ISB in Umeå!!
A new study from the Barandun research group in collaboration with researchers at The Rockefeller University and The Connecticut Agricultural Experiment station uncovers the cryo-EM structure of the smallest known eukaryotic cytoplasmic ribosome. The structure visualizes the effect of extreme genome compaction on the translation machinery in microsporidia, uncovers a species-specific ribosomal protein and suggests a novel mode of ribosome inhibition in eukaryotes.
Barandun, J., Hunziker, M., Vossbrinck, C. R. & Klinge, S. Evolutionary compaction and adaptation visualized by the structure of the dormant microsporidian ribosome. Nat. Microbiol. (2019). in press. doi:10.1038/s41564-019-0514-6
Involved research groups:
Barandun research group
The Laboratory for Molecular Infection Medicine Sweden (MIMS) and SciLifeLab National Fellow
Department of Molecular Biology
Laboratory of Protein and Nucleic Acid Chemistry, Klinge Lab
The Rockefeller University, New York, USA
Department of Environmental Sciences
The Connecticut Agricultural Experiment Station
New Haven, CT, USA
In a computational study by ISB member Kwangho Nam (Umeå and UT Arlington) and Martin Karplus (Harvard University) a detailed model has been developed for the coupling between rotary motion and ATP hydrolysis in F1-ATPase. The model predicts that F1-ATPase functions at near its maximum possible efficiency. The finding is published in PNAS. https://www.pnas.org/content/116/32/15924.long
In an ISB effort the research groups lead by Anna Linusson, Elisabeth Sauer-Eriksson and Magnus Wolf-Watz has discovered a key event in activation of the essential enzyme adenylate kinase. It was discovered that the large-scale and activating conformational change triggered by ATP binding is nucleated by a strong cation-PI interaction formed between the cationic sidechain of an arginine with the aromatic adenosine base of ATP. The discovery may pave way for future enzyme design efforts where recognition of aromatic systems is required. The finding was made possible through an integrative effort using DFT calculations, NMR spectroscopy and x-ray crystallography. The team consisted of Per Rogne, David Andersson, Christin Grundström, Elisabeth Sauer-Eriksson, Anna Linusson and Magnus Wolf-Watz. The finding is published in Biochemistry https://pubs.acs.org/doi/10.1021/acs.biochem.9b00538.
A fully funded PhD position is available in Karina Persson’s group. The overall aim of the project is to obtain structural and functional data of bacterial fimbrial proteins and associated proteins involved in maturation of fimbria For more information and how to apply:
The closing date for applications is the 5th of Aug. 2019.