Bio-membrane organization and function
Previous and Current Research
Biological membranes are highly complex composites of lipids, proteins and sugars. My aim is to understand how these molecular components organize into biological functional complexes that control fundamental processes such as signaling and sensing, energy conversion and electrical action potential propagation. To this end I pursue a biophysical approach: Compare complex cellular membranes to in vitro reconstituted model systems.
A key to a mechanistic understanding is the ability to observe membrane organization with a spatial resolution on the molecular level, a temporal resolution in the micro-second range and sensitivity down to the single molecule without disturbing the system (noninvasive). To reach this condition we combine fluorescence super-resolution methods (STED, SMLM) with the latest labelling technologies.
Lipid-protein interactions and self-organization
Simple lipid mixtures on its own already show fascinating self-organization behavior (phase separation, curvature, budding and fusion). However, in biological membranes regulation of structure and function arises from the interplay of proteins with lipids. The crux is these lipid-protein interactions are generally weak and transient which makes it very challenging to study. Even though transient and weak it is becoming more and more obvious that lipid protein interactions are the key for many regulatory processes in which specific protein complexes have to be formed for example upon stimuli during cell signaling. It is suspected that the composition of bio-membranes is specifically tuned to respond on these small stimuli with a local self-reorganization which induces and amplifies the (protein) function. Our goal is to understand the mechanisms which drive local self-reorganization in the membrane. Recent successful steps in this direction were for example identifying that hydrophobic mismatch and electrostatic interaction with the lipid PIP2 are driving the formation of active complexes of the SNARE protein synatxin-1 in plasma membrane. Additionally, we showed that pinning of membrane lipids and proteins by the cell cortex can induce local membrane reorganization dependent on the affinity of the pinning species.
Future Projects and Goals
Membrane organization at intercellular junctions
Starting my lab beginning of 2015 in Dresden we will focus on understanding the role of membrane organization during cell differentiation and tissue formation. To this end we will specifically analyze membrane organization at intercellular junctions and follow its assembly and regulation. As cellular junctions are one of the first specialized structures that form during tissue development they have a critical role in guiding cell polarization and differentiation. The junctions itself are highly enriched in specific proteins. However, very little is known about the lipids, the regulation and membrane organization at these sites. Our approach to understand the structure and the function of the junctions involves studying epithelial tissues in cell culture, semi-reconstituted cell junction in cells on micro-patterned surfaces and fully-reconstituted junction in model membranes.
Methodological and Technical Expertise
- Super-Resolution Microscopy (STED, SMLM)
- Fluorescence Correlation Spectroscopy, Single Molecule Tracking
- Membrane labelling (lipids and proteins) in vivo and in vitro
- Micro-Patterning of Surfaces for Control of Cell Attachment, Signaling and Differentiation
- Reconstitution of Membrane Proteins in Model Membranes
Alf Honigmann, Veronika Mueller, Haisen Ta, Andreas Schoenle, Erdinc Sezgin, Stefan W. Hell, Christian Eggeling
Scanning STED-FCS reveals spatio-temporal heterogeneity of lipid interaction in the plasma membrane of living cells.
Nat Commun. 2014 Nov 20;5:5412. doi: 10.1038/ncomms6412. (2014)
SK Saka, A Honigmann, C Eggeling, SW Hell, T Lang, SO Rizzoli
Multi-protein assemblies underlie the mesoscale organization of the plasma membrane.
Nat Commun. 2014 Jul 25;5:4509. doi: 10.1038/ncomms5509. (2014)
Alf Honigmann, Sina Sadeghi, Jan Keller, Stefan W. Hell, Christian Eggeling, Richard Vink
A lipid bound actin meshwork organizes liquid phase separation in model membranes.
Elife. 2014 Mar 18;3:e01671. doi: 10.7554/eLife.01671. (2014)
Alf Honigmann, Geert van den Bogaart, Emilio Iraheta, H Jelger Risselada, Dragomir Milovanovic, Veronika Mueller, Stefan Müllar, Ulf Diederichsen, Dirk Fasshauer, Helmut Grubmüller, Stefan W Hell, Christian Eggeling, Karin Kühnel & Reinhard Jahn
Phosphatidylinositol 4,5-bisphosphate clusters act as molecular beacons for vesicle recruitment.
Nat Struct Mol Biol. 2013 Jun;20(6):679-86. doi: 10.1038/nsmb.2570. Epub 2013 May 12. (2013)
Göttfert, F., C. A. Wurm, V. Mueller, S. Berning, V. C. Cordes, A. Honigmann, S. W. Hell
Coaligned Dual-Channel STED Nanoscopy and Molecular Diffusion Analysis at 20 nm Resolution.
Biophys J. 2013 Jul 2;105(1):L01-3. doi: 10.1016/j.bpj.2013.05.029. (2013)