Up to a third of all human genes encode membrane proteins — emphasizing both their variety and significance.
They are involved in a range of essential functions such as transporting molecules across the lipid bilayer and cell signaling. Importantly, many common human diseases (e.g., heart disease, neurological diseases, cancer and cystic fibrosis) are caused by mutations in membrane proteins, making them an extremely important target for drug development. This is highlighted by the fact that over 50% of current small molecule drugs target membrane proteins. For these reasons, the accurate study and analysis of membrane proteins is essential to enhancing our knowledge of human disease and the design of improved therapies.
Here are five of our favourite recent publications, highlighting some of the amazing research that is taking place in this important field.
1. New therapeutic targets for cystic fibrosis
Cystic fibrosis affects approximately one in 3,000 newborns of Northern European ancestry. It caused by mutations in the CFTR gene which encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This protein controls the flow of chloride (Cl-) and bicarbonate (HCO3-) ions in and out of cells. Mutation of the CFTR protein typically block the passage of these ions causing a buildup of thick mucus around the lungs, which increases the risk of pathogenic infection. Researchers from the University of Illinois have now demonstrated that amphotericin B, a small, naturally produced bacterial antifungal agent, can form an ion channel in lung epithelial cells, restoring ion transport to human and model animal cells exhibiting a range of CFTR mutations. This research provides proof-of-concept that small molecules can act as surrogates for defective transport proteins in human disease, opening the door to the development of new therapeutic strategies.
2. How to become a membrane protein
In a recent Science Advances publication, scientists at ETH Zurich describe their research into how proteins become embedded in cell membranes. Using single-molecule force spectroscopy (SMFS), whereby a tiny cantilever just a few nanometers thick is used to isolate molecules of interest, the team isolated the LacY protein from an Escherichia coli cell membrane. This molecule was then transferred to another membrane containing either one or both of two helper proteins (YidC – an insertase or SecYEG – a translocase). While it is known that these helper proteins support the insertion of membrane proteins, their precise mechanism had yet to be elucidated. The researchers were able, for the first time, to show how the insertase acts in a rapid but more random fashion when compared to the translocase which displays a more ordered, stepwise approach to protein insertion. These findings may support research into novel drug targets and the development of artificial cells, which could facilitate pharmaceutical production.
3. New insights into drug resistance
ABC transporters are a group of integral membrane proteins that use the energy stored in adenosine triphosphate (ATP) to transport substrates such as ions, amino acids, peptides and therapeutic drugs across the cell membrane. Members of this protein family are found across both prokaryotes and eukaryotes, and improved understanding of how these proteins export drugs from cells could deliver new insights into the development of drug resistance. Researchers from the University of Arkansas performed in silico molecular simulations to investigate how ABC transporters are affected by the lipid composition of the cell membrane. They discovered that the proteins were inactive and didn’t expel drugs in cell membranes comprising the phospholipid phosphocholine but the reverse was true for cell membranes comprising phosphoethanolamine. The differential activity was shown to be a result of conformational changes in the ABC transporter proteins caused by the different phospholipid composition. This information may support the development and testing of new antibiotics and cancer treatments.
4. Identification of a potential targets for treating Alzheimer’s disease
Tau is a microtubule-associated protein that regulates cytoskeleton dynamics, especially in neuronal cells. Phosphorylation and subsequent oligomerization of Tau is associated with a number of neurological diseases including Alzheimer’s. Misfolded and aggregated forms of Tau have prion-like properties allowing propagation from affected to unaffected cells. Although key in the propagation of Tau assemblies, the binding to and molecular interactions of exogenous Tau assemblies with the plasma membrane of neurons had not been fully characterized. Researchers in France have now discovered that, following lateral diffusion, fibrillar forms of Tau (Fib-Tau) cluster at excitatory synapses. The specific targets of Fib-Tau was shown to be sodium / potassium pump and glutamate receptors, which are essential for the survival of neurons. This research may support the development of new treatment strategies that prevent the binding of pathogenic tau aggregates to their neuron membrane targets.
5. Clearing out old or inactive membrane proteins
Researchers at Florida State University, recently published their work on how the inner nuclear membrane (INM) protein, Mps3, is cleared out once it has become inactive. MSP is essential to cell cycle progression and has been associated with diseases such as muscular dystrophy and progeria (a premature aging syndrome). Accumulation of MSP at the INM impairs nuclear morphological changes and cell division. The team discovered a novel mechanism of membrane protein degradation, involving the anaphase promoting complex/cyclosome (APC/C). It was revealed that APC/C controls degradation through the Mps3 N terminus, which resides in the nucleoplasm and possesses two putative APC/C-dependent destruction motifs.