Melanie McDowell – Membrane Protein Biogenesis
What molecular mechanisms control the delivery and correct insertion of membrane proteins at the endoplasmic reticulum?
We strive to obtain a molecular-level understanding of cellular pathways for the targeting and insertion of membrane proteins at the endoplasmic reticulum, using a multi-faceted structural, biophysical and biochemical approach.
Around one third of proteins in the eukaryotic cell are found in membranes, where they perform fundamental physiological roles and represent major drug targets. However, membrane proteins must first be delivered to and inserted into the correct membrane before they can function. For the vast majority of membrane proteins, the first stage in this journey is their synthesis in the cytosol and insertion into the endoplasmic reticulum (ER) membrane by cellular pathways. Such targeting and insertion pathways must overcome biophysical challenges created by the water insoluble transmembrane domains (TMDs) of membrane proteins. Initially, cytosolic targeting factors recognise and chaperone newly synthesised TMDs, preventing them from forming aggregates in the aqueous cytosol. Secondly, ER membrane insertases guide TMDs through the polar membrane surface and correctly orient them within the lipid bilayer.
Due to the huge repertoire of eukaryotic membrane proteins, different pathways are required for their ER targeting and insertion. Our work aims to elucidate the molecular mechanisms of these fundamental pathways, primarily through solving structures of their targeting factors and insertases by cryo-electron microscopy (cryo-EM) and X-ray crystallography. Using biophysical methods, in vitro reconstitution approaches and pull-outs of native protein complexes, we also work to understand how these components interact and ultimately the interplay between the different pathways.
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