Janine Brunner Lab

Research focus

Membrane proteins are mediators of essential processes in the cell such as solute transport, electrical excitability and signaling. Atomistic insight into the architecture of membrane proteins, their conformational breadth and precise functioning is essential in fundamental research. Since membrane proteins are major targets of small molecule drugs these insights are also necessary for the treatment of life-threatening diseases. In the Brunner lab we study the structure and function of membrane proteins, with a particular emphasis on lipid biology and ion channels in membrane transport. We apply biophysical, biochemical and structural biology methods such as single particle cryo-EM and X-ray crystallography. We further complement this information by investigating membrane protein activity in living cells by fluorescence microscopy and electrophysiology. 

Lipid transporters and membrane asymmetry
Our knowledge on the composition and architecture of biological membranes has grown substantially in the past decades. However, we are just beginning to functionally and structurally chara​​cterize the molecular identities that underlie the complex organization of bilayers. One important feature of biomembranes is the asymmetric distribution of specific lipids between the two leaflets of the bilayer. This distribution is also subject to dynamic changes and serves important functions. For instance, exposure of phosphatidylserine to the extracellular leaflet– normally confined to the intracellular leaflet of the plasma membrane in the resting state – is a crucial event in processes as diverse as apoptosis, blood clotting, bone mineralization, myoblast fusion and in cell to cell spreading of viruses (apoptotic mimicry). 

We are interested in the origin and significance of membrane lipid asymmetry in bilayers throughout the cell and its concerted breakdown as signaling cue. In our research activities we focus on membrane proteins that impact the organization of the lipid bilayer, in particular lipid transporters that contribute to membrane lipid asymmetry and scramblases that randomize the distribution of lipids between the leaflets. We investigate how certain lipid species reach their destination in a distinct leaflet of the bilayer, why lipid asymmetry is important in membranes and which functions are elicited through the concerted breakdown of this asymmetry by scramblases.  To address such questions, we structurally describe lipid transporters to reveal their ‘inner workings’ and regulation. The subcellular localization of these transporters in order to understand the cellular function as well as the network of interacting proteins is another emphasis. Our efforts aim to contribute to a deeper understanding of the involved proteins in lipid trafficking and signaling in healthy and pathological conditions.

Ion channels 
In the second line of research we investigate ion channels, particularly of intracellular membranes like the lysosome. The lysosome is the cellular recycling machinery and is increasingly recognized as sensor for the metabolic state of the cell. It is the destination membrane for fusion with autophagosomes, large vesicles that form de novo in the cytosol to enclose solutes and proteins in bulk for subsequent degradation in this recycling organelle. This interplay makes lysosomes thus also pivotal for the removal of protein aggregates from the cytosol and connects them to neurological diseases like Parkinson disease. Ionic currents and gradients across the lysosomal membrane are fundamental for the proper functioning of the lysosome, e.g. for volume regulation, setting of the membrane potential and for maintenance of a low luminal pH, making ion channels important regulators of transport, fusion and the degradation of lysosomal contents. Consequently, modulation of ion channel activity in these organelles holds great prospects for medical applications. In our lab, we strive to understand how lysosomal ion channels achieve selectivity and how they are gated to open or close. We further investigate the significance of ion gradients across the lysosomal membrane for the turnover of autophagosomes and maintenance of the luminal pH.  

Method development and drug discovery
Besides our basic research activities, we develop methodologies to greatly reduce the required biomass and sample consumption for the determination of membrane protein structures by cryo-EM. Further, our research is aiming for the development of platforms to screen for small molecule modulators of membrane protein activity.   

Publications

Preparation of Proteoliposomes with Purified TMEM16 Protein for Accurate Measures of Lipid Scramblase Activity.Brunner Janine Denise@ Schenck StephanMethods in Molecular Biology, 1949, 181-199, 2019@: corresponding authors
Structural basis for ion selectivity in TMEM175 K+ channelsBrunner Janine D@ Jakob Roman* Schulze Tobias* Neldner Yvonne Moroni Anna Thiel Gerhard Maier Timm Schenck Stephan@BIORXIV, doi.org/10.1101/480863 , , 2018* or °: authors contributed equally@: corresponding authors
Structural basis for anion conduction in the calcium-activated chloride channel TMEM16A.Paulino Cristina Neldner Yvonne Lam Andy Km Kalienkova Valeria Brunner Janine Denise Schenck Stephan Dutzler RaimundeLife, 6, e26232, 2017
Structural basis for phospholipid scrambling in the TMEM16 family.Brunner Janine* Schenck Stephan* Dutzler RaimundCURRENT OPINION IN STRUCTURAL BIOLOGY, 39, 61-70, 2016* or °: authors contributed equally
X-ray structure of a calcium-activated TMEM16 lipid scramblase.Brunner Janine Lim Novandy Schenck Stephan Duerst Alessia Dutzler RaimundNATURE, 516, 207-12, 2014

Job openings

Janine Brunner

Janine Brunner

Research area(s)

Bio

PhD: University of Zürich, Department of Biochemistry, Zürich, Switzerland, 2015
Postdoctoral Fellow: University of Zürich, Department of Biochemistry, Zürich, Switzerland, 2016
Postdoctoral Fellow: University of Basel, Biozentrum, Basel, Switzerland, 2017                                
Postdoctoral Fellow: Paul Scherrer Institute, Laboratory of Biomolecular Research, Switzerland, 2018-2019
Group Leader: VIB-VUB Center for Structural Biology, Brussels, Belgium

Contact Info

VIB-VUB Center for Structural BiologyBuilding EPleinlaan 2 1050 BRUSSELRoute description