How mechanical stimuli trigger cellular signalling
International GPCR research collaboration deciphers structure of active receptors

Date:
April 14, 2022
Source:
Universita"t Leipzig
Summary:
Breathing, seeing, hearing -- the family of G protein-coupled
receptors (GPCRs) is involved in a variety of physiological
processes and is also the cause of diverse diseases. Some members
of the GPCR family respond to mechanical stimuli. Researchers have
now achieved a milestone on the way to understanding the mechanism
by which this receptor class is activated.

They were able to describe the structure of specific active
receptors.



FULL STORY ========================================================================== Breathing, seeing, hearing -- the family of G protein-coupled receptors
(GPCRs) is involved in a variety of physiological processes and is also
the cause of diverse diseases. As has now been discovered by a team of scientists led by Professor Ines Liebscher from Leipzig University, some members of the GPCR family respond to mechanical stimuli. In collaboration
with Chinese research groups, they have achieved another milestone on
the way to understanding the mechanism by which this receptor class is activated. For the first time, they were able to describe the structure
of specific active receptors. Their findings have now been published in
the journalNature.


========================================================================== "GPCRs are involved in almost all physiological processes in the
body. GPCRs allow humans to see, control their immune system, direct
hormone balance," explained Professor Ines Liebscher from the Rudolf Scho"nheimer Institute of Biochemistry at the Faculty of Medicine,
emphasising: "They have been the focus of our research for many years
now, and research on GPCRs is of such outstanding importance because
the majority of approved drugs target this receptor family." GPCRs are receptors that transmit their signals via so-called G proteins, which
is why they are also called G protein-coupled receptors -- or GPCRs
for short.

The researchers in Leipzig focus their work on a special class of
receptors, known as adhesion GPCRs. In collaboration with several
Chinese teams of scientists, the research groups led by Professor
Ines Liebscher and Professor Torsten Scho"neberg have now been able to
describe the structure of special receptor molecules in their active
state. This data supports findings from seven years ago at the Leipzig institute that these receptors are activated by a tethered agonist
within the molecule. Furthermore, the Leipzig researchers showed that mechanical stimuli play a crucial role in the activation by the tethered agonist. It is still not fully understood how our body's own cells are
able to interpret mechanics -- in the form of vibration, gravitational
forces, relative cell movement or swelling -- as a signal. "Our research
has established the basis for our partners from China to structurally
elucidate a scenario of how mechanical stimuli are recognised in the
molecule and transmitted as signals," said Liebscher, a medical scientist
and biochemist.

"The results can be found in the current study." Functional nature of mechanosensitive receptors elucidated "About one-third of the GPCR family
are still orphans, meaning that either their function or activation is
unknown. With our current research, we have made a decisive contribution
to better understanding GPCR structures," said co- author Scho"neberg,
director of the Rudolf Scho"nheimer Institute of Biochemistry. "The new
study findings are of landmark importance when it comes to developing
future forms of therapy," concluded Liebscher. She is a member of the
steering committee in the EU-funded COST Action Adher'n Rise CA18240,
which she successfully secured in 2019. This network of scientists from
28 European countries aims to promote, stimulate and implement research on adhesion G protein-coupled receptors (aGPCRs) "from bench to bedside." The latest findings and approaches to adhesion GPCR research will also be
presented at the international conference 4GPCRnet, of which Professor Liebscher is co- organiser. This high-level meeting will be held on 26
to 29 September 2022 on Leipzig University's Augustusplatz campus.

The current research project is part of Collaborative Research Centre 1423 "Structural Dynamics of GPCR Activation and Signaling," a research network funded by the German Research Foundation, led by Leipzig University
and also involving the Martin Luther University Halle-Wittenberg,
Charite' - - Universita"tsmedizin Berlin and the Max Delbru"ck Center
for Molecular Medicine. Researchers with backgrounds in biochemistry, biomedicine and computational science collaborate across the boundaries
of their respective institutions and disciplines for a comprehensive understanding of the structure and dynamics of GPCRs.


========================================================================== Story Source: Materials provided by Universita"t_Leipzig. Original
written by Peggy Darius.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yu-Qi Ping, Peng Xiao, Fan Yang, Ru-Jia Zhao, Sheng-Chao Guo,
Xu Yan,
Xiang Wu, Chao Zhang, Yan Lu, Fenghui Zhao, Fulai Zhou, Yue-Tong Xi,
Wanchao Yin, Feng-Zhen Liu, Dong-Fang He, Dao-Lai Zhang, Zhong-Liang
Zhu, Yi Jiang, Lutao Du, Shi-Qing Feng, Torsten Scho"neberg,
Ines Liebscher, H. Eric Xu, Jin-Peng Sun. Structural basis for the
tethered peptide activation of adhesion GPCRs. Nature, 2022; DOI:
10.1038/s41586-022- 04619-y ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220414110756.htm

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