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THE PAPER

A.S. Smith et al., “Myosin IIA interacts with the spectrin-actin

membrane skeleton to control red blood cell membrane curvature

and deformability,” PNAS, 115:E4377–85, 2018.

Healthy red blood cells are puffy with a dimpled middle. “It’s just a

really cool shape,” says Velia Fowler, a cell biologist at The Scripps

Research Institute in San Diego. For decades, researchers have

been wondering what gives red blood cells their characteristic

curves, and now Fowler and her colleagues have the answer: myo-

sin proteins tug on the red blood cell’s cytoskeletal membrane,

creating a divot at the center.

Back in the 1980s, when Fowler started working with red blood

cells, it wasn’t clear whether they even contained myosin. She sus-

pected they might, because the protein appeared to play a role in giv-

ing other cells their shapes. After painstaking experiments, Fowler

finally showed that red blood cells do carry the protein, but exactly

how it influenced erythrocytes’ shape remained a mystery. “We didn’t

have the tools to do those experiments then,” she says. The myosin

filaments in red blood cells are tiny, only around 200 to 450 nano-

meters long, making them extremely challenging to image. And the

first inhibitor of myosin IIA—the specific protein found in red blood

cells—wasn’t developed until the early 2000s, so scientists couldn’t

see what happened when the protein wasn’t functioning in the cells.

In the new study, the team attached an immunofluorescent tag

to myosin and a phalloidin tag to actin in human red blood cells

and observed the cells with both superresolution and total internal

reflection fluorescence microscopy. Filaments of myosin attach to

filaments of actin and the scaffolding protein spectrin that lie just

beneath and parallel to the cell membrane, the team found. When

myosin and actin interact and myosin contracts, the cell membrane

stiffens, giving the cell a dimple at its center. Inhibiting the motor

activity of the protein causes the myosin filaments to expand so

they no longer tug on spectrin and actin. That leads to less tension

in the membrane and, ultimately, the disappearance of the dimple.

By expanding and contracting, the myosin filaments likely make

it possible for red blood cells to shape-shift as they tumble in the

bloodstream’s shear flow and squeeze through microvessels such as

capillaries, then pop back into their dimpled form, Fowler says.

This discovery could also give clues to how myosin works in

other types of cells, Vann Bennett, a biochemist at Duke Uni-

versity who was not involved in the new study, tells The Scien-

tist. “Red blood cells are a true experiment of nature,” he says.

“They’ve gotten rid of the cell nucleus, mitochondria, and all

cytoskeletal proteins.” These simplified cells “have been a pow-

erhouse for generating concepts about how [plasma] mem-

branes are organized in other cell types,” Bennett explains.

Understanding the importance of myosin’s contraction in

shaping red blood cells, he says, may help in teasing out its

functions in other cell types.

Another recent study supports myosin’s widespread impor-

tance in maintaining cell structure: the research showed the

protein is critical for axons to grow and shape themselves, sug-

gesting it could be involved in brain plasticity (Neuron 97:P555–

70.E6, 2018). —Ashley Yeager © KIMBERLY BATTISTA

54 THE SCIENTIST | the-scientist.com

The Literature

CELL & MOLECULAR BIOLOGY

In the Blood

EDITOR’S CHOICE PAPERS

IN A PINCH: In healthy red blood cells (RBCs), myosin fibers (blue) contract,

pulling on actin (pink) and spectrin proteins (purple) connected to the cell

membrane and helping to give the cells their distinct, indented shape (top).

When the myosin fiber is experimentally manipulated so that it slackens or

detaches from the cell-membrane proteins, red blood cells instead take on

an oval shape (bottom).

Healthy RBC

Myosin-inhibited RBC

Spectrin

Actin Myosin

contraction

relaxed