Research

Introduction

Being essential to biological processes membrane proteins display a variety of functions. They play important roles in all three kingdoms of life, e.g., in signal transduction, communication between cells, nutrient transport, stress response and metabolic processes. Many mammalian membrane?proteins were identified as targets for drug discovery as their dysfunction has been involved with multiple severe diseases,?such as?diabetes, cancer, Alzheimer's disease, hypertension, or epilepsy.

Structural Biology aims to decipher the molecular working mechanism of membrane proteins by combining atomic structures in different conformational states with functional and dynamical characterization. Research on membrane proteins is still very challenging and requires strong resources and the sophisticated combination of different biochemical and biophysical methods.

In the Biophysics II?department, we have established the infrastructure for state-of-the-art Structural Biology on Membrane Proteins in order to investigate different transport protein families.

1. The BCCT family (betaine‐choline‐carnitine‐transporter) comprises sodium‐ or proton‐coupled secondary transporters (e.g. BetP and BetT respectively) that are ubiquitous in microorganisms. These transporters accumulate compatible solutes ensuring a physiologically acceptable level of cellular hydration and turgor at high osmolarity in many bacteria. They represent osmotically controlled uptake systems scavenging compatible solutes from scarce environmental sources as effective osmoprotectants. The glycine betaine transporter BetP from Corynebacterium glutamicum is a representative for osmoregulated symporters of the BCCT family and functions both as an osmosensor and osmoregulator. To date it is one of the best characterized regulated secondary transporter.

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2. Solute carrier (SLC) transporters have important roles in physiological processes. As SLC transporters are involved in both rare and common diseases they have a strong impact in developing new therapeutic approaches.

SLC transporter function is still enigmatic on a molecular level. New SLC families have been identified and atomic structures and molecular models of SLC transporters are increasingly available. We are working also in collaboration with the Preclinical and the Clinical Medicine Departmentts on transporters of the SLC1, SLC5, SLC6, SLC20 and SLC25 families, respectively.

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3. The Transient Receptor Potential (TRP) channel superfamily comprises cation permeable channels that are grouped into six subfamilies. E.g., the canonical TRP (TRPC) subfamily contains the founding member of mammalian TRP channels and the polycystic TRP (TRPP) subfamily comprises channels involved in autosomal dominant polycystic kidney disease (ADPKD). TRP channels are involved in a variety of physiological and pathophysiological processes making the study of these channels imperative to our understanding of subcellular biochemistry.

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4. Mechanosensitive channels (Msc) belong to a class of ion channels which respond to mechanical stress within a lipid bilayer of the membrane. They sense alterations in osmotic and mechanic pressures imposed onto the membrane and respond by channel opening. Thereby they enable the physiological relevant ions to diffuse passively in order to alter electrochemical and substrate gradients. Two types of Msc can be distinguished according to the levels of conductance they generate: mechanosensitive channels of small (MscS) and large conductance (MscL). For both types of channels, crystallographic data are available and cryo-EM will provide new structural information in the future. We are mainly working on archaeal and bacterial MscS homologues.