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A protein puppet show: Scientists show how cortex proteins pull strings to control cell surface functions

Read time: 4 mins
Proteins on the cell membrane

Proteins on the cell membrane
[Image Credits: M Uhlen, P Oksvold, L Fagerberg, E Lundberg, K Jonasson, M Forsberg, M Zwahlen, C Kampf, K Wester, S Hober, H Wernerus, L Björling, F Ponten (2012) CIL:40476, Homo sapiens, osteosarcoma. CIL. Dataset.]

It is mesmerising to watch synchronised swimming. In this water sport, the swimmers perform ballet-like acts in sync with each other in a water pool. They come together momentarily to form patterns, say a flower or a star, and then disperse. A similar ‘synchronised dance’ plays out on the cell membrane—an envelope surrounding our cells.

Different proteins on cell membranes come together to form a protein complex. They perform essential functions like receiving nutrients cargo from outside and bringing them inside the cells, interacting with chemicals and relaying relevant information crucial for the cell response to the environment, engaging with viruses or acting as receptors for specific signals. Once their part is done, the proteins disperse.

Studies have shown that another set of proteins called cortex present below the cell membrane plays a crucial role in controlling the above protein complexes. However, the exact mechanism of these activities and how the cortex packs the proteins has remained unclear.

In a recently published study, researchers have solved a vital puzzle about how the cortex network is arranged. Using a 3- dimensional matrix in a computer simulation and an artificial membrane mimicking a cell membrane, they find that two important cortex proteins, myosins and actins have to be stacked one above the other to pack efficiently. The study, conducted by Simons Centre for the Study of Living Machines, National Centre for Biological Sciences (TIFR), Bengaluru, was published in Science Advances.

“The arrangement of proteins on the cell surface is of vital importance because several important functions of the cell depend on it,” says Dr Madan Rao, a professor at the National Centre for Biological Sciences (NCBS), Bengaluru. “Since the architecture of the cortex controls it, it becomes important to understand how the cortex itself is arranged in three dimensions,” he adds.

Cortex is present just under the cell membrane and comprises a different network  of proteins. This network  is below the cell membrane but connects with  the proteins above the membrane. Studies have shown that two vital cortex proteins, actin and myosin, play the role of a puppeteer controlling the activity of proteins above and below the cell membrane. Actin and myosin are physically connected to some intermediate proteins that, in turn, bind and steer the movements of other proteins on the cell surface. In short, a cell can regulate what happens on its surface by pulling strings from under the membrane.

In the cortex, actin molecules form rope-like structures and are pulled by myosins. Myosins have projections that bind to the actin fibres, and by changing their shapes and angles, they pull the actin fibre. 

The researchers used a STED microscope, a powerful instrument that gives fluorescent images of cellular proteins at high resolution. They observed how myosin molecules huddle together, separated by just a few nanometers (a billionth of a metre.  Human hair is about 40,000 nanometers thick, for comparison). Myosin molecules have a bulky head and a lighter long tail. This massive head, in theory, prevents them from coming to a close huddle. Researchers ran a computer simulation to see how actin and myosin molecules meet, move, and bump into each other. But the puzzle remained.

“When we put realistic sizes of actin and myosin into the two-dimensional simulation, myosin molecules would bump into each other and be difficult to pack at nanometer scales because they were bulky,” explains Dr Rao.

The researchers then proposed a three-dimensional field in the computer simulation instead of the two-dimensional one. The simulation now packed the heavy and bulky myosin heads in different layers, one below the other – an arrangement not visible in two-dimensional simulation–   which also agreed with the observations.

The researchers verified the new arrangement on an artificial membrane made of two layers of fat to test their theoretical concept. Darius Koster, a postdoctoral researcher at NCBS, built this membrane. Under the STED microscope, they could see myosin and actin indeed arranged in different layers, enabling the stacking of myosin heads. This work, which started as a theoretical computer simulation, was verified with an experiment on an artificial cell membrane.

This current study solves a vital puzzle on the architectural distribution  of myosin and actin under cell membranes. It emphasises the necessity of a three-dimensional matrix to mimic cellular happenings – an arrangement critical in orchestrating the formation of protein complexes on cell surfaces.