With over 40,000 different types, lipids are essential components of all cells.
They play a key role in storing energy, cell signaling, and as structural components of cellular membranes. Lipids predominantly function through interaction with proteins, and these interactions are of interest to researchers across a variety of disciplines, including pharmaceutical research, for which over 60% of drug targets are located at the cell surface or other cellular membranes. Despite their importance, many protein-lipid interactions are poorly understood and authors in the literature comment that further work is needed to fully investigate these interactions.
Here we look at three examples from the literature where the interaction between proteins and lipids had a huge impact
Defeating the influenza virus
The Centers for Disease Control and Prevention (CDC) estimate that in 2017/18 almost 50 million people suffered with flu, caused by infection with the infuenza virus; resulting in ~23 million medical visits, ~1 million hospitalizations and ~80,000 deaths in the United States alone.
Recently scientists at the University of Maine, USA, have identified an interaction between the cytoplasmic tail of the viral hemagglutinin (HA) protein with the host cell lipid PIP2. The relative stability of the HA cytoplasmic tail may allow the development of long-lasting antiviral therapies which have, so far proven elusive for this rapidly evolving pathogen.
G-protein-coupled receptors (GPCRs) and lipid interactions
GPCRs are the largest and most diverse set of membrane receptors in eukaryotes. These integral membrane proteins have a key role in cell signaling and can respond to diverse external stimuli, including light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters.
Researchers have now revealed that membrane lipids can modulate (enhance or decrease) the activity and oligomerization of GPCRs. The GPCR A2AR plays a key role in the heart and brain by regulating oxygen consumption and blood flow. It has also been identified as a potential therapeutic target for the treatment of Alzheimer’s and Parkinson’s disease.
Recent research has shown how cholesterol in cell membranes can interact with the surface of A2AR, reducing the binding of its antagonist ligand ZM241385. Such studies open the door to the potential manipulation of membrane lipids to modulate GPCR activity.
Lipid-transfer proteins (LTPs)
A commonly overlooked form of protein-lipid interaction is that of soluble proteins with lipids outside of a cellular membrane. An example of this can be found in lipid-transfer proteins (LTPs), which, as the name suggest, can transfer lipids within the cytoplasm from one membrane-bound organelle to another – for example, between the endoplasmic reticulum (ER) and mitochondria.
It has been shown that many LTPs shield the hydrophobic potions of the lipid within internal cavities of the protein, allowing them to be transported across the cytoplasm. There are a large number of LTPs which can interact with different lipids. In addition to transferring lipids, LTPs have also been shown to modify lipids and present them to other proteins.
Studying the interaction of LTPs with lipids is challenging and, as yet, the function and specific pathway of many LTPs remain unknown.
Protein-lipid interactions and amyloids
Amyloids (aggregated proteins) are associated with a number of neurodegenerative diseases, including Parkinson’s, Alzheimer’s and Huntingdon’s disease. Aggregates of the 140-amino acid protein α-synuclein (αSyn), which is abundantly expressed in neurons, are central to the pathogenesis of Parkinson’s disease (PD).
It has been shown that αSyn interacts with lipid membranes and that this interaction influences αSyn structure and subsequent fibril formation. One hypothesis is that membrane binding of the protein may alter the protein conformation, inducing the formation of a “seed” or aggregation-prone oligomers.
Recent research has revealed that high levels of oleic acid promote the aggregation of αSyn, while triglycerides, inhibit this action. Disruption of the stearoyl-CoA-desaturase enzyme, which is key in the production of oleic acid, also protected against αSyn toxicity. These findings may enable the development of novel treatments for Parkinson’s and other neurodegenerative diseases.
As outlined above, the importance of protein-lipid interactions is becoming increasingly apparent; however, to date, this field of research has been hampered by a lack of simple, informative analysis tools.
For researchers wishing to quickly assess protein-lipid interactions, the Fluidity One-W allows accurate quantification of interactions (based on the change in size of the protein vs protein-lipid complex) from just 5 µL input material using microfluidic diffusional sizing (MDS).