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A research team at Leipzig University has identified a mechanism in adhesion G protein-coupled receptors (adhesion GPCRs), a specific group of membrane receptors. This mechanism is essential for the activity of many of these receptors. The study, published in Nature Communications, shows that a specific interaction between two amino acids is indispensable for the self-cleavage of these receptors. This insight could pave the way for new therapies for cancer, neurological disorders and inflammatory diseases associated with malfunctioning adhesion GPCRs.
G protein-coupled receptors (GPCRs) serve as docking sites and transmit signals within cells, and are also the most important class of proteins in pharmacology: around one third of all approved medicines act via them. One subgroup of these receptors that has not yet been exploited for drug development is the adhesion GPCRs (aGPCRs). Their role is to detect mechanical forces, for example during interactions between cells. The hallmark of adhesion GPCRs is their GAIN domain.
This protein unit contains a region that can “cut” or cleave itself. This self-cleavage – also known as autoproteolysis – is a key step in activating the function of many aGPCRs. It occurs within a sequence of three amino acids (histidine, any amino acid, and serine or threonine), whose composition normally determines whether cleavage takes place.
The researchers investigated this mechanism in the aGPCR receptor BAI2 (brain-specific angiogenesis inhibitor 2), which plays a role in neurobiology and in the formation of blood vessels. This receptor has the unusual property that, despite having what appears to be a cleavage-prone sequence, biochemical analyses have characterised it as non-cleaving, or only cleaving extremely slowly: without external influences, the receptor takes around 100 days to cleave itself. To understand this phenomenon, Professor Norbert Sträter from the Institute of Bioanalytical Chemistry and his colleagues analysed the three-dimensional structure of the receptor’s GAIN domain using X-ray crystallography. They found that a key interaction required for cleavage is missing. Under normal circumstances, the amino acids histidine and phenylalanine interact via what is known as a π–π interaction, which is necessary for protein cleavage. However, this interaction is absent in BAI2.
Further molecular dynamics simulations carried out by Professor Peter Hildebrand and his team at the Institute of Medical Physics and Biophysics showed that this π–π interaction is important because it enables the GAIN domain to adopt a wide range of protein conformations that provide suitable starting points for the chemical cleavage reaction. They also found that aGPCRs contain two highly flexible loop regions near the cleavage site, which may help ensure that the interactions required for cleavage can occur.
Building on this knowledge, the researchers led by Professor Norbert Sträter and Professor Tobias Langenhan at the Rudolf Schönheimer Institute of Biochemistry were able to modulate self-cleavage in BAI2. They replaced the loop regions and introduced a phenylalanine residue, which enabled the cleavage reaction in BAI2 to occur in less than two days. The study shows that structural differences, the flexibility of the GAIN domain loops and π–π interactions all influence self-cleavage. At the same time, the researchers found that some aGPCRs can function without undergoing cleavage.
“Our results show that cleavage in adhesion GPCRs depends not only on the chemical sequence, but also on structure and protein dynamics,” summarises Professor Sträter. “This is a crucial step towards understanding how these receptors are activated – and how they might be targeted.”
These findings shed new light on the complex mechanisms of aGPCRs and represent an important step towards a better understanding of these receptors and their role in various conditions. In the long term, this could lead to new treatment approaches. aGPCRs hold considerable potential for the development of new drugs. Current research aims to identify molecules that can modulate receptor signal transduction – that is, communication between cells – potentially also by binding to the unique GAIN domain.
The structure, dynamics and function of GPCRs are the overarching focus of Collaborative Research Centre 1423 at Leipzig University, which enabled the joint research carried out in this project.
Prof. Dr. Norbert Sträter
Leipzig University
Telephone: +49 341 97-31311
strater@bbz.uni-leipzig.de
Prof. Dr. Peter Hildebrand
Leipzig University
Telephone: +49 341 97-15712
peter.hildebrand@medizin.uni-leipzig.de
https://www.nature.com/articles/s41467-026-71225-1
"Structural basis of GAIN domain autoproteolysis and cleavage-resistance in the adhesion G-protein coupled receptors”, DOI: 10.1038/s41467-026-71225-1
https://research.uni-leipzig.de/sfb1423/
Three amino acids (shown in turquoise) are ideally positioned for self-cleavage of the protein chain ...
Source: N. Sträter
Copyright: Illustration created using PyMOL and Blender/Leipzig University
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