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RTG Biomembranes

Projects

Interactions at biological membranes such as binding to, transport through and along, or aggregation at membrane surfaces are intimately coupled to the molecular structure and dynamics of the membrane. This project aims at characterizing the structure and dynamics of biological membranes in the presence and absence of membrane-spanning proteins. In particular, the degree and length scale of ordering effects of membrane proteins of varying composition and size on their phospholipid environment, the formation of nano-scale membrane domains, and the environment-dependent co-existence of different phases will be addressed. Neutron scattering experiments and both atomistic and coarse-grained molecular dynamics simulations will yield a complementary view on these processes, with both high spatial and temporal resolution.

Groups:

Computational Biology Division (Böckmann)

Crystallography and Structural Physics (Unruh)

The transport and dynamical structuring of lipids and proteins in biological membranes is one of the most fundamental processes in living cells. While a wealth of data has emerged in investigations of related biological processes, the general biophysical principles underlying complex diffusion and reorganisation in a membrane are still not well understood. Here we develop reconstituted model systems that reproduce the cellular conditions in a well controlled manner. Combining input from single-particle experiments and simulations we address the transport and complexation in membranes. We specially focus on lipid translation and rotation in supported and suspended membranes, membrane transmitted cooperative effects between proteins leading to intermolecular recognition, domain growth, and active processes. Our aim is to provide an understanding of the interplay between these effects on related length and time scales.

Groups:

Max Planck Institute for the Science of Light (Sandoghdar)

Theoretical Physics (Smith)

Sphingosine-1-phosphate (S1P) protects the endothelium and maintains vascular integrity. S1P circulates in the blood stream bound to apolipoprotein M (ApoM). Despite previously obtained atomistic insight into the structure of ApoM with bound S1P little is known about the lipid uptake mechanism by ApoM and the lipid release. It is e.g. unclear whether ApoM directly interacts with the S1P receptor to deliver S1P or whether S1P is first released into the receptor membrane and subsequently diffuses to the receptor. The project combines ITC measurements, X-ray crystallography, and multi-scale molecular dynamics simulations to elucidate the molecular mechanisms of ligand release in ApoM and ligand binding to the S1P receptor, taking different membrane compositions into account.

Groups:

Biotechnology (Muller)

Computational Biology (Böckmann)

G protein-coupled receptors (GPCRs) are a large family of the integral membrane proteins, which emerged as major target for the development of novel drug candidates in all clinical areas. Although lipid bilayer components are known to alter the physiological profiles of many membrane proteins, the role of the lipid bilayer composition in GPCR signaling remains elusive. Both atomistic and coarse-grained molecular dynamics simulations as well as experimental state-of-the-art biophysical and biochemical methods using either cells or supported lipid bilayers of different compositions will be applied to address this question. We expect to obtain detailed information on the influence of lipid domains, membrane fluidity, unsaturated lipids, and different lipid headgroups on the receptor function.

Groups:

Computational Biology (Böckmann)

Max Planck Institute for the Science of Light (Sandoghdar)

Signaling by Wnt-family proteins plays a crucial role in patterning, differentiation and morphogenesis during embryonic development and in adult tissue organization. Pathological disorders in the adult, including cancer, often correlate with aberrant Wnt signaling. Wnts are ligands of the Frizzled receptor family and their signaling activity is further modulated by co-receptors such as LRP5/6 or Receptor-Tyrosine-Kinase like proteins such as Ror2. LRP6 and Ror2 are regulated by the same kinases and are able to move between different membrane microdomains. It is currently unknown if and how the localization to particular membrane microdomains affects the signaling capability of Ror2 or how this differential localization is regulated. According to current models, the length and amino acid sequence of the transmembrane domain and membrane-proximal regions are crucial for the interaction of membrane proteins with lipid microdomains. For Wnt co-receptors the molecular mechanisms that regulate shuttling between different membrane microdomains and their relation to signaling activity remain elusive. Deciphering these regulatory mechanisms will provide further insight into the mechanisms that control Wnt signaling activity and specificity.

Groups:

Biotechnology (Muller)

Developmental Biology (Schambony)

Dendritic cells express a variety of endocytic receptors which are responsible for the defence against invading pathogens. The aim of this project is to shed light in the differential distribution of endocytic receptors in the membrane of murine and human Dendritic cells. Those receptors were found to be suitable target receptors for the in vivo delivery of antigens thereby implying high clinical therapeutic options in the field of cancer treatment. Therefore, we want to investigate receptor compartmentalization, and internalization processes with advanced life-cell imaging methods (TIRF, confocal microscopy), fluorescence correlation spectroscopy (FCS) and mathematical modelling; thus allowing us to further understand the functions of these receptors.

Groups:

Dermatology (Dudziak)

Medical Physics and Technology (Fabry)

Tobacco pollen tube tip growth is an excellent experimental system to investigate directional cell expansion. This process is essential for plant morphogenesis and depends on local secretion of cell wall material, which needs to be compensated by endocytic membrane uptake. Current models suggest that apical secretion and lateral endocytosis create a retrograde flow within the plasma membrane at the pollen tube tip. We have identified regulatory proteins and lipids, which specifically associate with distinct plasma membrane domains, and have important but only partially understood functions in the control of apical membrane traffic and pollen tube tip growth. The aim of this project is to characterize molecular and cellular mechanisms responsible for the maintenance of the specific association of different regulatory proteins with distinct domains of the highly dynamic pollen tube plasma membrane. An important focus of the project is the role of differentially distributed regulatory membrane lipids in these mechanisms.

Groups:

Cell Biology (Kost)

Max Planck Institute for the Science of Light (Sandoghdar)

Theoretical Physics (Smith)

Tetraspanins (TETs) are small transmembrane proteins that have emerged in animals as key players in numerous cellular processes including membrane trafficking, signaling, morphogenesis, motility as well as cell adhesion and fusion. The function of TET proteins is linked to their ability to laterally associate with each other and to engage in a wide range of specific molecular interactions with signaling proteins as well as with sterols and other lipids. These interactions result in the formation of a distinct class of membrane domains, the tetraspanin-enriched microdomains (TEMs), which function as signaling platforms. Although 17 TETs are expressed in the model plant Arabidopsis thaliana, hardly anything is known about TET functions in plants. As TETs mediate cell adhesion and control membrane trafficking in animals, we will test whether TETs have similar functions in plant cells and thereby regulate polar cell growth.

Groups:

Cell Biology (Dettmer)

Medical Physics and Technology (Fabry)

The vacuole of plant cells is required for volume regulation and turgor pressure formation during growth processes. Although the vacuolar membrane is not directly exposed to large pressure changes, it responds readily to external osmotic challenges. Changes in ion fluxes precede and accompany the rearrangements of the vacuolar architecture during osmo- and volume regulation. The nature of the osmosensor(s) and the mechanisms of ion flux regulation under osmotic stresses remain largely unclear. This project employs biochemical, cell and molecular biological tools as well as electrophysiological techniques in order to identify the mechanisms involved in regulation of this vital process and to better understand the coordination between transport processes at the vacuolar and plasma membrane.

Groups:

Cell Biology (Kost)

Plant Cell Biology (Dietrich)

The stability of a tissue emerges from the balance of forces that are mediated by the cell membrane by interactions with the extracellular matrix as well as with the neighboring cells. It has long been proposed that tissues behave as liquids in the limit of zero frequency, and possess a characteristic surface tension, which arises as a collective, macroscopic property of groups of mobile, cohering cells. Recent work has demonstrated that the ratio of cell-matrix adhesion to cortical tension determines tissue surface tension and predicts the shapes of aggregate surface cells based on the feedback between mechanical energy and geometry. Current models, however, are unable to predict the dynamics of such cell shape changes. The aim of this project is to understand how cell-matrix adhesion, cortical tension and cytoskeletal rheology govern cell shape, cell migration and the positional time dependent correlations between neighboring cells.

Groups:

Medical Physics and Technology (Fabry)

Theoretical Physics (Smith)

In recent years, a stress-induced regulator of diverse physiologic functions – Neuropeptide Y (NPY) – was shown to play crucial roles in chronic liver disease (Dietrich et al., 2013, Hartl et al., 2015, Moleda et al., 2011). NPY receptors are membrane bound G-Protein coupled receptors (GPCRs) and were found to be overexpressed in cancers, emerging more and more as promising therapeutic targets (Li et al., 2015).

Recently, one NPY-receptor was shown to co-function with the receptor tyrosine kinase (RTK) neurotrophic receptor tyrosine kinase 2 (TrkB), resulting in a novel GPCR-RTK transactivation with strong implications on cancer cell survival and chemoresistance (Czarnecka et al., 2015). However, the exact mechanism of such a specific GPCR-RTK transactivation remains largely unclear. Moreover, the co-clustering of GPCRs and RTK (i.e. TrkB) in lipid microdomains and lipid rafts as well as its potential impact on cancer cell signaling is unknown and will be addressed in this study.

Therefore, the aims of this study are:

1)     Unraveling the functional and therapeutic relevance of a GPCR-RTK crosstalk in cancer cells

2)     Mapping and co-localization of NPY-receptors and RTKs in lipid microdomains/lipid rafts

3)     Defining molecular interactions of NPY-receptor homo- and hetero-dimerization

 

Groups:

Biochemistry and Molecular Medicine (Bosserhoff)

Computational Biology (Böckmann)

Medical Physics and Technology (Fabry)

Developmental Biology (Schambony)