Gatekeepers of the living cell

Living cells are little fortresses by themselves, defended by a biological membrane called the cell membrane. In 1972, a classical model (fluid mosaic model) was proposed describing the membrane as a lipid layer in which the proteins are floating. The scientists who put forward the theory noticed how the components within the membrane are moved by thermodynamic forces. But the nitty-gritty of the movement and inter-molecular communications remained obscure. Since then, various theories were proposed and discarded.

In the late 1990s, Satyajit Mayor and his colleagues at the National Centre for Biological Sciences, Bengaluru, found tiny lipid raft-like nanostructures, which they felt, would have played a key role in carrying the signals across the membrane. The rafts are special compartments in the membrane that help organise the signalling molecules and eventually carry the signals through a complicated biochemical process.

The NCBS biologist collaborated with his physicist colleague Madan Rao, synthetic chemist Ram Vishwakarma at the Indian Institute of Integrative Medicine, Jammu and Zhongwu Guo at Wayne State University. More than a decade later, Satyajit and his co-workers dug more into these tiny lipid rafts. “We now know how these nanoscale structures are built and how they function, though a few pieces of the puzzle still remain unsolved,” Satyajit says.

The need for more

After nine years of research, the team finally defined the role of a long chain lipid molecule called Phosphatidyl Serine (PS) that plays a vital role in carrying the signals across. The discovery would lead to a better understanding of how a cell controls local lipid environment in the membrane. This is a fundamental requirement for the regulation of how signals are read and interpreted by the cell.

“It provides us a new handle to look at disease biology and opens up a window to look for new drug targets in future. Receptor proteins are common drug targets and function of receptors are controlled by membranes. The receptors can be modulated through membranes,” explains Ram. Drug targets are molecular components in a cell, whose function can be influenced by an external chemical — the medicine — to prevent manifestation of a particular disease.

Satyajit, however, thinks it is too early to talk about drug targets as more research is necessary. “But it would provide a better understanding of diseases like diabetes, in which dietary lipids play a key role. We would be able to understand how lipids and fats impact on cellular signalling,” he avers.

In addition, illnesses like prion diseases and several cardiovascular diseases may also become tractable. Understanding how these membrane lipids, the ‘gatekeepers of the cell’, function may also help deter the progression of viral diseases by disrupting the interaction of membrane components with viruses.

“The uniqueness of the study lies in discovering a specific role for PS in nanocluster formation, a building block of lipid rafts and how the chemistry of both the outer and inner leaflet facilitate this process,” says Anupama Ambika Anilkumar, one of the authors of the paper published in Cell.

An array of methods from biology, genetics, chemistry and physics were combined to carry out the experiments that offered explanation on the creation of nanoclusters. Some researchers believed the nanoclusters of lipids were formed on the membrane by a random combination of lipids. This study, however, shows that the formation of these lipid clusters is a very active process, which is templated by the actin (a protein) cytoskeleton at the inner leaflet of the cell membrane. The question is: how do lipids on the outer surface ‘talk’ to the actin on the inner leaflet when they cannot reach across the bilayer?

Something new

“The sum of the experimental and theoretical studies amounts to a convincing argument for a new mechanism of nanocluster formation,” says a commentary by Erdinc Sezgin, Simon J Davis and Christian Eggeling from the Weatherall Institute of Molecular Medicine, University of Oxford. The commentary was also published in the same issue of Cell.

Examining the biochemical process at the nanoscale, the team identified PS as the lipid on the inner leaflet that reaches out to the other side to mediate the communication between actin and lipid-anchored proteins on the outer leaflet. It is a key component in membrane signalling dynamics and its absence can lead to several defects in cell signalling, which can lead to improper cell spreading and migration phenotypes.

This understanding also points to further clues about the role of these clusters. They have been hypothesised to function as a ‘sorting station’ for components to be recruited for signalling events on the cell surface. The identification of PS leads to the next step in understanding how the clusters function and identifying what proteins are involved in binding to actin. “The new work addresses only the formation of clusters of long-acyl-chain-containing lipid anchored proteins, which may not as yet, exemplify a general organising principle. However, it is possible that processes similar to these (depicted by the Indian team) have an important role in the formation of other membrane assemblies,” suggests the Oxford team.

Ongoing experiments in Satyajit’s lab are aimed at completing other aspects of this picture, namely the nature of communications across the cell membrane and the components at the inner leaflet responsible for holding the PS species, and exploring how these mechanisms may result in large scale lipidic domains. These entities are deployed in numerous cell functions and are therefore, important questions to tackle.