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Christian Löw

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Membrane Protein Structural Biology

"Starting your own research group is always a great challenge. I chose CSSB because it offers a great scientific environment, ideal for establishing collaborations and working on new methods and challenging projects."

Christian Löw, CSSB Group Leader

Previous and current research
The Löw group focuses on structural and functional studies of membrane transport proteins. Combining high throughput technologies for structural studies with classical biochemical approaches has enabled us to obtain a first glimpse of the structure and function of nutrient uptake systems. We seek to develop a better understanding and visualization of the molecular processes of substrate recognition and transport in nutrient uptake systems.

Structure of a proton dependent oligopeptide transporter (POT) in the inward open conformation. Reference: Structural insights into substrate recognition in proton-dependent oligopeptide transporters, Guettou F, Quistgaard EM, Trésaugues L, Moberg P, Jegerschöld C, Zhu L, Jong AJ, Nordlund P, Löw C. (2013), EMBO Rep. 14(9):804-810. doi:10.1038/embor.2013.107

Cell membranes compartmentalise metabolic processes and serve as selective barriers for permeation. Therefore, nutrient transport through the plasma membrane conducted via membrane transport proteins is essential to maintain homeostasis within the cell. Many proton-coupled secondary active transporters of the major facilitator superfamily (MFS) are involved in the accumulation of nutrients above extracellular levels. Structural and functional analyses of MFS transporters suggest an alternating-access mechanism for the transport of substrates across the membrane. Here the transporter adopts different conformational states, allowing the substrate binding site to face either side of the membrane. A full transport cycle involves at least three different conformational states – inward open, occluded and outward open –, with each of them in a ligand-bound and ligand-free state. Since MFS transporters are found in all branches of life and often with numerous gene copies, we believe that many if not all of these transporters follow a common transport mechanism.

We study proton coupled oligopeptide transporters of the PepT family (also known as the POT family) which are responsible for the uptake of a range of different di- and tripeptides, derived from the digestion of dietary proteins, and are highly conserved in all kingdoms of life. The best studied members of this family include the two human peptide transporters, PepT1 and PepT2. These peptide transporters are of great pharmacological and pharmaceutical interest as they accept a number of drugs and amino acid-conjugated pro-drugs as substrates. A detailed understanding of the structural basis for substrate recognition can therefore help to convert pharmacologically active compounds into substrates for PepT1 and PepT2 and improve their absorption in the small intestine and subsequent distribution in the body. We therefore study the proton-dependent oligopeptide transporter (POT) family using a combination of biochemical and biophysical methods.

Structural differences between the inward open and occluded state structures of the sugar transporter XylE. The structures were overlayed and the transmembrane helices (TM) are labeled and arrows designate changes in the position of the helices upon opening of the transporter towards the cytoplasm. Reference: Structural basis for substrate transport in the GLUT-homology family of monosaccharide transporters, Quistgaard EM, Löw C, Moberg P, Trésaugues L, Nordlund P. (2013), Nat. Struct. Mol. Biol. 20(6):766-768. doi:10.1038/nsmb.2569

Integral membrane proteins are a challenging class of proteins in terms of their structural and functional characterisation. Over the years, we have developed and established new tools as well as a workflow for protein production and quality control of membrane proteins including functional assays. This allows us to screen multiple samples and parameters in parallel. Furthermore, we are trying to find new ways to stabilise integral membrane proteins in vitro upon extraction from their natural lipid environment.

Future projects and goals
To obtain comprehensive insights into the transport mechanism of this transporter class, we focus our research on characterising nutrient transporters from bacteria, parasites and humans in various states of the transport cycle using structural methods to decipher the common transport mechanism of MFS transporters. We aim to obtain new structural and dynamic insights into the binding mode of transporters to peptides, drugs, and inhibitors and to provide molecular insights into structure and function of transport regulators of nutrient transporters.

Selected Publications
Frauenfeld, J., et al. (2016) A novel lipoprotein nanoparticle system for membrane proteins. Nature Methods 13, 345-51

Quistgaard EM, et al. (2016) Understanding transport by the major facilitator superfamily (MFS): structures pave the way. Nature Reviews Molecular Cell Biology 17, 123-32

Guettou F, et al. (2014) Selectivity mechanism of a bacterial homolog of the human drug-peptide transporters PepT1 and PepT2. Nat. Struct. Mol. Biol. 21, 728-31

Quistgaard EM, et al. (2013) Structural basis for substrate transport in the GLUT-homology family of monosaccharide transporters. Nat. Struct. Mol. Biol. 20, 766-8

Guettou F, et al. (2013) Structural insights into substrate recognition in proton-dependent oligopeptide transporters. EMBO Rep. 14, 804-10



Picture: © Marta Mayer
Drucker