Essential immune protein resolved
Immune proteins: IgM is the larger, incomplete hexagon shape, AIM is the smaller broad bean shape inside the wedge-shape gap. AIM is more easily recognized as the bright white, broad-bean-shaped spot (right). [Hiramoto et al., originally published in Science Advances]
Using negative stain electron microscopy, Japan-based researchers have revealed the structure of the essential immune protein, immunoglobulin M.
The breakthrough creates future possibilities to develop more effective medicines for a range of illnesses from cancer to neurological diseases.
"We'll have to revise the textbooks," says researcher leader, Professor Toru Miyazaki from the University of Tokyo.
Miyazaki and colleagues, verified the structure of natural immunoglobulin M (IgM) using mouse and human versions of the protein.
IgM is now understood to be shaped like an incomplete hexagon, or a pentagon with a wedge-shaped gap.
All data were acquired with a JEOL JEM-2010F electron microscope operated at 200 kV using a Tietz 4k by 4k complementary metal-oxide semiconductor camera.
Data processing was performed using the Scipion software package.
IgM is the first immune system protein that develops in the human foetus and remains the first responder to pathogens throughout life.
The structure of IgM was first identified in 1969 as a "five-pointed, star-shaped table" and updated in 2009 to be a five-sided dome or "mushroom cap."
"The original IgM model was made by looking at a few individual molecules by hand with what today we think is a low-resolution microscope," highlights Miyazaki. "Now we have clearer pictures and the computer can examine thousands of individual IgM molecules."
Since identifying the correct shape of IgM, researchers now understand that the inactive protein, apoptosis inhibitor of macrophage (AIM), is nestled inside the gap of the IgM incomplete hexagon.
The structural connection between IgM and AIM means that drugs with the ability to regulate the release of AIM could be used to create AIM-based disease therapies.
"We can think of AIM as a fighter jet and IgM as the aircraft carrier ship. When other molecules activate the immune system, IgM releases AIM. The much smaller AIM protein goes around the body to clear away damaged cells and prevent disease," explains Miyazaki.
The incomplete hexagon structure is still only a 2D understanding of IgM structure, so Miyazaki and colleagues will continue to carry out additional analyses and hope to report the 3D structure of IgM soon.
Research is published in Science Advances.