Melanie McDowell: Membrane protein biogenesis at the endoplasmic reticulum

Melanie McDowell: Membrane protein biogenesis at the endoplasmic reticulum

*Coming February 2022!*

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.

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Positions at all levels (Postdoctoral researcher, doctoral student, technician) will soon be available to become part of a multi-disciplinary, collaborative team. Interested individuals should contact with a CV and brief letter of motivation.

Our focus

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.

Selected Publications

1.
M. A. McDowell*, M. Heimes* and I. Sinning
Structural and molecular mechanisms for membrane protein biogenesis by the Oxa1 superfamily
Nat Struct Mol Bio 28, 234-239 (2021)
2.
M. A. McDowell, M. Heimes, F. Fiorentino, S. Mehmood, Á. Farkas, J. Coy-Vergara, D. Wu, J. Reddy Bolla, V. Schmid, R. Heinze, K. Wild, D. Flemming, S. Pfeffer, B. Schwappach, C. V. Robinson and I. Sinning
Structural basis of tail-anchored membrane protein biogenesis by the GET insertase complex
Molecular Cell 80 (1), 72-86.e7 (2020)
3.
M. A. McDowell*, A. M. P. Byrne*, E. Mylona, R. Johnson, A. Sagfors, V. F. Crepin, S. M. Lea and G. Frankel
The S. Typhi effector StoD is an E3/E4 ubiquitin ligase which binds K48- and K63-linked diubiquitin
Life Science Alliance 2(3), e201800272 (2019)
4.
M. A. McDowell, J. Marcoux, G. McVicker, S. Johnson, Y. Fong, R. Stevens, L. A. H. Bowman, M. T. Degiacomi, J. Yan, A. Wise, M. E. Friede, J. L. P. Benesch, J. E. Deane, C. M. Tang, C. V. Robinson and S. M. Lea
Characterisation of Shigella Spa33 and Thermotoga FliM/N reveals a new model for C-ring assembly in T3SS
Mol Microbiol 99, 749-766 (2015)
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