The Institute of Clinical Physiology / Div. of Nutritional Medicine is part of the Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie at the Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin
Postdoc position - Molecular architecture of tight junctions and paracellular ion channels
Tight Junctions regulate paracellular permeability for solutes and water in epithelia and endothelia and are essential for tissue barriers. On the one hand, transient opening of tight junctions could improve drug delivery across tissue barriers, e.g. the intestinal epithelium or the blood brain barrier. On the other hand, stabilization of pathologically altered tight junctions could recover the protective function of a compromised tissue barrier (e.g. in inflammatory bowel disease). To achieve this, the transmembrane claudin proteins are promising targets, since they form the backbone of tight junctions and determine their paracellular barrier properties.
In the project, claudin structure-function relationships will be characterized to elucidate the molecular mechanism of paracellular permeability regulation by claudins. Aim is, in particular, to clarify the molecular architecture of tight junctions and how claudins interact with each other at cell-cell contacts to form intramembranous polymers which – in a claudin subtyp-dependent manner – either tighten the paracellular gap or form size- and charge-selective channels.
The following methods will be applied: (a) structural bioinformatics: homology modeling of claudin protein structures, oligomer docking and especially molecular dynamics simulations of membrane-embedded claudin oligomers; (b) experimental: cell culture, transfection, cellular reconstitution von tigh junction strands/polymers, confocal and STED super resolution microscopy, live cell imaging, FRET, FRAP, site-directed mutagenesis, freeze-fracture electron microscopy, Western blot, chemical protein crosslinking, measurement of paracellular ion- and tracer permeability
PhD in biochemistry, bioinformatics, biology, biophysics, biotechnology or related field of study and strong interest in structural and functional cell biology. Experience in structural bioinformatics or biochemical/cell biological structure-function studies is of advantage.
What we offer:
We offer a strong, committed and enthusiastic scientific environment at the interface between basic and preclinical research. Optional: Association with DFG Research Training Group "TJ-Train", GRK 2318 (http://klinphys.charite.de/grk).
How to apply:
For application (please via email) and further information please contact: Priv.-Doz. Dr. Jörg Piontek phone 030/450-514535, e-mail: email@example.com, Institut für Klinische Physiologie, Charité, Hindenburgdamm 30, 12203 Berlin. For more Information, see https://klinphys.charite.de and project-related publications:
1. Hempel et al., 2020. Assembly of Tight Junction Strands: Claudin-10b and Claudin-3 Form Homo Tetrameric Building Blocks that Polymerise in a Channel-Independent Manner. J Mol Biol. pii: S0022-2836(20)30222-9. doi: 10.1016/j.jmb.2020.02.034
2. Piontek et el., 2020. Molecular architecture and assembly of the tight junction backbone. Biochim Biophys Acta., 1862(7):183279. doi: 10.1016/j.bbamem.2020
3. Rosenthal et al., 2019. Claudin-15 forms a water channel through the tight junction with distinct function compared to claudin-2. Acta Physiol (Oxf). 228(1):e13334. doi: 10.1111/apha.13334
4. Neuhaus et al., 2018. Reversible opening of the blood-brain barrier by claudin-5-binding variants of Clostridium perfringens enterotoxin's claudin-binding domain. Biomaterials 161: 129-143
5. Klar et al. , 2017. Paracellular cation permeability due to a rare CLDN10B variant causes anhidrosis and kidney damage. PLoS Genet;13(7):e1006897.doi: 10.1371/journal.pgen.1006897
6. Milatz S et al., 2015. Probing the cis-arrangement of prototype tight junction proteins claudin-1 and claudin-3. Biochem. J. 468(3): 449-458
7. Piontek et al., 2008. Formation of tight junction: determinants of homophilic interaction between classic claudins. FASEB J. 22:146-158