Les scientifiques ont révélé la structure moléculaire de l’un des récepteurs immunitaires les plus importants

Les chercheurs ont découvert la structure moléculaire exacte du récepteur des cellules IgM de type B.

Des chercheurs de Fribourg et de l’Université de Harvard ont découvert la structure tridimensionnelle du récepteur de l’antigène des cellules B et ont acquis de nouvelles connaissances sur sa composition.

Les cellules B ont des récepteurs antigéniques à leur surface qui leur permettent d’identifier les agents pathogènes envahissants tels que les bactéries et les virus. Lorsque le récepteur des cellules B se lie à un antigène, c’est-à-dire une structure étrangère, la cellule B est activée, déclenchant la production d’anticorps. Les anticorps sont très importants pour la survie humaine car ils nous protègent des maladies graves, telles que les infections par des agents pathogènes[{” attribute=””>COVID-19. Vaccines provide protection by activating antigen receptors, triggering an immune response.

An international collaboration of researchers from the University of Freiburg’s Cluster of Excellence CIBSS and Harvard Medical School in the United States has recently revealed the exact molecular structure of an IgM-type B cell receptor. Their results suggest that the B cell’s surface receptor interacts with other receptors, thus controlling signal transduction. The findings were recently published in the prestigious journal Nature.

Structure of the IgM B Cell Receptor

Structure of the IgM B cell receptor of the mouse. Credit: Hao Wu/Harvard Medical School

Connection of Signaling Subunits with the Immunoglobulin

The B cell antigen receptor is made up of an antibody linked to the cell membrane as well as two smaller proteins known as Ig alpha and Ig beta. When the B cell receptor detects a pathogen, these smaller subunits transmit signals to the cell’s interior.

“Exactly how these signaling subunits are connected with the immunoglobulin was previously unknown,” says Prof. Dr. Michael Reth from the University of Freiburg’s Faculty of Biology, who has been conducting research on the receptor for over 30 years and originally discovered its signaling subunits. He is a member of the Cluster of Excellence CIBSS – Centre for Integrative Biological Signalling Studies and co-director of the Cluster of Excellence BIOSS.

“For a long time, we did not have the technical possibilities to study the exact structure of membrane proteins. Now, cryo-electron microscopy has enabled us to create a high-resolution image of the B cell receptor,” says Reth.

With cryo-electron microscopy, the sample to be studied is cooled very rapidly to minus 183 °C. This reduces the natural movement of the molecules and prevents the formation of tiny ice crystals that otherwise would destroy the protein structure. In this way, it is possible to achieve resolutions that are many times higher than with other electron microscopic methods. In their current study, the researchers achieved a resolution of 3.3 ångströms, which corresponds to the width of just a few atoms. To do so, they combined hundreds of thousands of images of the entire receptor with those of a truncated version that lacked two flexible regions. They then used these data to calculate the complete three-dimensional structure of the B cell receptor on the computer.

A symmetrical membrane-bound antibody binds only on one side

The striking thing about the three-dimensional structure is that the symmetrical membrane-bound antibody only binds to Ig alpha and Ig beta on one side, thus forming an asymmetrical complex. This asymmetry resembles that of the T cell receptor, another important immune receptor whose structure was first elucidated in 2019. “It is astounding that both types of antigen receptor form asymmetrical complexes,” explains Reth. “This leads us to conclude that the structure now elucidated is part of a larger receptor complex and that it interacts with still other molecules on the B cell surface.”

Such larger structures, which are held together through less powerful forces, cannot yet be studied with techniques like cryo-electron microscopy. However, the newly published molecular structure provides further evidence in favor of such an interaction with other molecules: It shows that the outside of the B cell receptor contains conserved

Amino acids are a set of organic compounds used to build proteins. There are about 500 naturally occurring known amino acids, though only 20 appear in the genetic code. Proteins consist of one or more chains of amino acids called polypeptides. The sequence of the amino acid chain causes the polypeptide to fold into a shape that is biologically active. The amino acid sequences of proteins are encoded in the genes. Nine proteinogenic amino acids are called “essential” for humans because they cannot be produced from other compounds by the human body and so must be taken in as food.

” data-gt-translate-attributes=”[{” attribute=””>amino acids. Amino acids are described as conserved if they hardly change in the course of evolution and are therefore identical in the antigen receptors of different organisms. “The presence of conserved amino acids that are directed outward suggests that the IgM B cell receptor has further binding partners,” says Reth. “In other words, we only know part of the machine so far – and now we want to identify the other building blocks and determine how they influence the signaling effect of the receptor.”

These other building blocks could explain how the receptor is normally kept quiescent and is activated only when it binds to an antigen. “That will be one of the next important tasks in the study of adaptive immunity,” summarizes Reth. “A better understanding of B cell activation could also help us to further improve the development of vaccines or to understand the formation of lymphoma in which the B cell receptor is activated in an uncontrolled manner.”

Reference: “Structural principles of B cell antigen receptor assembly” by Ying Dong, Xiong Pi, Frauke Bartels-Burgahn, Deniz Saltukoglu, Zhuoyi Liang, Jianying Yang, Frederick W. Alt, Michael Reth and Hao Wu, 13 October 2022, Nature.
DOI: 10.1038/s41586-022-05412-7

The study was funded by the National Institutes of Health (NIH) and the German Research Foundation (DFG).

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