Neurodegenerative disease, diabetes and cancer are pressing health concerns in modern society, and in part are related to disruptions in the composition and asymmetric distribution of lipids within the biological membrane. Such changes are typically a result of dysfunction in lipid metabolism and/or impaired protein driven lipid transport . To date, there is a major knowledge gap regarding the basic biology of lipid transport and their role in the aforementioned diseases. Our goal is to identify new pathways and strategies to address changes in lipid homeostasis in health and disease.
We apply a "bottom-up" approach by asking fundamental questions regarding protein driven lipid transport and metabolism and use biochemistry, biophysics and structural biology (cryo-electron microscopy and crystallisation) to identify and understand the molecular mechanisms at the atomic and cellular levels.
Our research is supported by the Lundbeck Foundation and the Aligning Science across Parkinson's (ASAP) Initiative.
Biological membranes are bilayers composed of a broad range of glycerophospholipid and sphingolipid species. A striking aspect of eukaryotic membranes is the uneven distribution (asymmetry) of different lipid species across the bilayer. This lipid asymmetry is not restricted to the plasma membrane as organelles of the late secretory pathway also display a non-random distribution of their constitutive lipids, which potentiates the membrane and is crucial to a range of membrane processes such as vesicle biogenesis, tuning of immune response, signalling and the regulation of membrane protein function. Given its central role in cell biology it is unsurprising that impaired lipid asymmetry has been associated with human disease including neurodegenerative diseases such as Parkinson’s (PD) and Alzheimer’s (AD), as well as cancer and diabetes.
The generation and maintenance of lipid asymmetry, requires the action of specific lipid transporting proteins fuelled by chemical energy (ATP), termed lipid flippases and lipid floppases. Lipid flippases belong to the P-type ATPase superfamily and the majority of lipid flippases exist as multi-subunit proteins, comprising a P4-ATPase and an auxiliary protein from the CDC50 family. The P4-ATPase subunit translocates phospholipids and select glycosphingolipids from the exoplasmic/lumenal leaflet to the cytoplasmic leaflet of the membrane.
The long-term objective of the lab is to elucidate the molecular determinants of substrate specificity, the role of the CDC50 protein and flippase regulation by intrinsic auto-regulatory elements and interaction partners. To accomplish this, we study both mammalian and yeast lipid flippases through a combination of cryo-electron microscopy, biochemistry and cell biology.
The major facilitator superfamily (MFS) constitute the largest known superfamily of secondary active transporters. These transporters are responsible for translocating a broad range of substrates (ions, amino acids, peptides and lipids), either along their concentration gradient or uphill using the energy stored in the electrochemical gradients.
We are interested in studying how these integral membrane proteins interact with and transport hydrophobic/lipidic substrates, whose functions are required for cell signalling and the enzymatic biosynthesis and modification of cellular membranes.
For more information about these projects please contact Joseph Lyons (lyons@mbg.au.dk)
