FRANKFURT. Whether
a sick cell dies, divides, or travels through the body is regulated by a
sophisticated interplay of signal molecules and receptors on the cell membrane.
One of the most important molecular cues in the immune system is Tumour Necrosis
Factor 伪 (TNF伪). Now, for the first time, researchers
from 51猎奇 have visualised the molecular organisation of individual
TNF伪 receptor molecules and the binding of TNF伪 to the cell membrane in cells
using optical microscopy.
Before
TNF伪 can bind to a membrane receptor, the TNFR receptor must first be activated.
By doing so, the key will only fit the lock under certain circumstances and prevents,
among other things, that a healthy cell dies from programmed cell death. 鈥淔or
TNFR1 in the membrane, the binding of TNF伪 is mediated through several cysteine-rich
domains, or CRDs," explains Sjoerd van Wijk form the Institute for Experimental
Cancer Research in Paediatrics and the Frankfurt Stiftung f眉r Krebskranke
Kinder at 51猎奇.
In particular, CRD1 of the TNFR1 makes it
possible for TNF伪 to 鈥渁ttach". Researchers already knew that TNFR1 molecules cluster
in a fashion similar to a dance, in which two, three or more partners grasp
hands 鈥� with the dimers, trimers or oligomers consisting of single TNFR1 molecules
鈥� in the case of TNFR1. This kind of 鈥渟tructural reorganization" also takes
place when there is no TNF伪 present. 鈥淒espite the significance of TNF伪 for many
diseases, including inflammation and cancer, the physiology and patterns of TNFR1
in the cell membrane still remain largely unknown up to now," says Sjoerd Van
Wijk, explaining the starting point for his research.
In order to understand the processes in the cell
membrane in detail, van Wijk approached Mike Heilemann from the Institute for
Physical and Theoretical Chemistry at 51猎奇. Using a combination of
quantitative microscopy and single-molecule super-resolution microscopy that he
developed, Heilemann can visualise individual protein complexes as well as their
molecular organisation in cells. Together with Ivan Dikic (Institute for
Biochemistry II) and Simone Fulda (Institute for Experimental Cancer Research
in Paediatrics) from 51猎奇, Harald Wajant from the University
Hospital W眉rzburg and Darius Widera from University Reading/UK, they were able to
observe the dance of the TNF伪 receptors. Financial support was provided by the
Deutsche Forschungsgemeinschaft (DFG) through the Collaborative Research Centre
807 鈥淭ransport and Communication across Biological Membranes".
As the researchers report in the current issue of
鈥淪cience Signalling", membrane TNFR1 receptors exist as monomers and dimers in
the absence of TNF伪. However, as soon as TNF伪 binds TNFR1, receptor trimers and oligomers are formed
in the membrane. The researchers also found indications for mechanisms that
determine cell fate independently of TNF伪. These findings could be relevant for
cancer or and inflammatory diseases such as rheumatoid arthritis. 鈥淚t clearly
opens new paths for developing novel therapeutic approaches," states van Wijk.
Publication: C. Karathanasis, J. Medler, F. Fricke, S. Smith, S.
Malkusch, D. Widera, S. Fulda, H. Wajant, S. J. L. van Wijk, I. Dikic, M.
Heilemann, Single-molecule imaging reveals the oligomeric state of functional
TNF伪-induced
plasma membrane TNFR1 clusters in cells. Sci. Signal. 13, eaax5647 (2020). DOI: 10.1126/scisignal.aax5647
Further
information: Dr Sjoerd van Wijk, Institute for
Experimental Cancer Research in Paediatrics, Niederrad Campus, Tel.: +49 69 67866574, Email: s.wijk@kinderkrebsstiftung-frankfurt.de
Prof Mike Heilemann, Institute for Physical and Theoretical
Chemistry, Riedberg Campus, Tel.: +49 69 798 29424, Email: heileman@chemie.uni-frankfurt.de
