Only now have scientists cracked the molecular structure of one of the most important receptors in the immune system

The surface of B cells is covered with antigen receptors, which they use to recognize invading pathogens such as bacteria and viruses
.
When the B cell receptor binds to the antigen, that is, to the foreign structure, the B cell is activated and triggers the production
of antibodies.
Antibodies are essential for our survival and protect us from serious illness
caused by infections with pathogens such as COVID-19.
Vaccines are protective because they activate antigen receptors, which trigger an immune response
.
An international team of researchers from the University of Freiburg and Harvard Medical School's Outstanding CIBSS Cluster has now published the exact molecular structure
of an IgM-type B cell receptor.
Their findings suggest that receptors on the surface of B cells interact with other receptors and thus control their signal transduction
.
The study was published in the prestigious journal Nature

Connection of signaling subunits to immunoglobulins

The B-cell antigen receptor consists of
an antibody bound to the cell membrane and two smaller proteins, Ig α and Ig β.
Once the B-cell receptor recognizes the pathogen, these smaller subunits transmit signals inside
the cell.
Prof.
Michael Reth, from the Faculty of Biology at the University of Freiburg, said: "Exactly how these signaling subunits are connected to immunoglobulins was previously unknown
.
Professor Michael Reth has been studying this receptor for more than 30 years and initially discovered its signaling subunit
.
He is a member of the Cluster of Excellence at the CIBSS Center for Integrated Biosignaling Research and co-director
of the BBSS Cluster of Excellence.
"For a long time, we didn't have the technical possibility to study the exact structure
of membrane proteins.
Now, cryo-electron microscopy allows us to create high-resolution images of B cell receptors," Reth said
.

Under a cryo-electron microscope, the sample to be studied is rapidly cooled to minus 183°C
.
This reduces the natural movement of molecules and prevents the formation of Xiaoice microcrystals that would otherwise destroy the protein structure
.
In this way, it can achieve many times higher resolution
than other electron microscopy methods.
In their current study, the researchers achieved a resolution of 3.
3 ångströms, which is equivalent to the width
of several atoms.
To do this, they combined
complete images of hundreds of thousands of receptors with truncated versions missing two flexible regions.
They then used the data to compute the complete three-dimensional structure
of the B cell receptor on a computer.

Symmetrical membrane-bound antibodies bind on only one side

The striking thing about this three-dimensional structure is that this symmetrical membrane-binding antibody binds only to the Ig α and Ig β on one side, thus forming an asymmetric complex
.
This asymmetry is similar to that of T cell receptors, another important immune receptor whose structure was first elucidated
in 2019.
Reth explains: "It's
shocking that these two types of antigen receptors form an asymmetric complex.
This leads us to conclude that the structure now elucidated is part of a larger receptor complex that interacts
with other molecules on the surface of B cells.
”

This larger structure is held together by smaller forces and cannot yet be studied
with techniques such as cryo-electron microscopy.
However, the newly published molecular structure provides further evidence for this interaction with other molecules: it suggests that the outside of the B cell receptor contains conserved amino acids
.
If amino acids change little during evolution and are therefore identical in antigen receptors in different organisms, they are called conserved amino acids
.
"The presence of outwardly oriented conserved amino acids suggests that the IgM B cell receptor has further binding partners," Reth said
.
"In other words, until now, we only knew one part of the machine, and now we want to identify the other components and determine how they affect the signaling effect of the receptor.
"

These other building blocks could explain why the receptor normally remains quiescent and is only activated
when it binds to an antigen.
"This will be one of the next big tasks in adaptive immunity research," concludes
Reth.
"A better understanding of B-cell activation could also help us further improve vaccine development, or understand the formation
of lymphomas where B-cell receptors activate in an uncontrolled way.
"

Structural principles of B-cell antigen receptor assembly