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FRIMEDBIO-Fri med.,helse,biol

Life at the periphery: the workings of proteins at the surface of cell and organelle membranes

Alternative title: Bioinformatikk av proteiner som fungerer på overflaten av celler og organellmembraner

Awarded: NOK 9.6 mill.

In this project we are trying to better understand how some proteins stick to and work at the surface of the cell membranes. The cell membrane delimits the cell and contains all its elements, a little bit like a pouch. There are membranes also around the organelles in a cell, for example around the endoplasmic reticulum or the Golgi apparatus. We now know that the cell and organelle membranes are much more than just inert pouches: they are permeable thanks to the presence of channels and transporters but what is perhaps less known is that their surfaces are the stage of many biochemical reactions. These membranes consist mostly of phospholipids (fat molecules) which arrange as a double layer, exposing their polar head at the surface while their fatty hydrophobic tails arrange inside the membrane. It results that the surface of these membranes have chemical and physical properties that differ from the inside of a cell, and so the proteins working at the membrane surface need to be somewhat different from other proteins. Unfortunately we know very little about these differences and because of that we cannot predict which proteins are able to bind to cell membrane. In addition it makes it very difficult to develop drug candidates to would target this type of proteins. In this project we develop models and software for predicting the behavior of proteins binding and working at the surface of the cell and organelle membranes. The models are built from physics and chemistry principles, and the calculations and simulations have proven to be useful to learn more about how protein structures and dynamics in general, and in particular to how proteins bind to cell membranes. This will enable the prediction of whether or not a protein has the necessary properties to stick to cell membranes. We will also be able to describe the mechanisms by which certain proteins accomplish their function at the cell and organelle membranes.

Peripheral membrane proteins (PMPs) are soluble proteins that bind to the surface of membranes and are key players in a myriad biological processes, including signalling and lipid metabolism. They accomplish a variety of critical functions thanks to their exquisite resolution in time and space, enabling them to recognize specific lipid composition and distinguish between different organelle membranes. PMPs include membrane anchoring domains such as C2 or PH domains, but also proteins achieving complex biochemical processes at the membrane interface such as enzymes and lipid-transfer proteins which requires the exquisite recognition of specific lipids in the membrane. Unlike protein-protein or protein-DNA interfaces, protein-membrane interfaces of PMPs are poorly characterized, understood and predicted. Building on our leading expertise and competitive edge in both computational and experimental methods for the study of PMPs, we will combine multiscale molecular simulations, deep learning, and high-throughput biochemical membrane binding assays to fill the knowledge gap, extract atomic-level understanding, and develop predictive capability. This will unlock high-impact downstream opportunities in biology and medicine, such as the possibility to tailor-make PMPs with desired properties and to design, rationally, inhibitors for protein-membrane interfaces.

Funding scheme:

FRIMEDBIO-Fri med.,helse,biol

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