Amazing stuff!
"Cells are enveloped by a lipid membrane that gives them structure and provides a barrier between the cell and its environment. However, evidence has recently emerged suggesting that these membranes do more than simply provide protection — they also influence the behavior of the protein receptors embedded in them.
A new study ... adds further support to that idea. The researchers found that changing the composition of the cell membrane can alter the function of a membrane receptor that promotes proliferation.
Epidermal growth factor receptor (EGFR) can be locked into an overactive state when the cell membrane has a higher than normal concentration of negatively charged lipids, the researchers found. This may help to explain why cancer cells with high levels of those lipids enter a highly proliferative state that allows them to divide uncontrollably. ..."
From the eLife assessment and abstract:
"eLife Assessment
The authors describe an interesting approach to studying the dynamics and function of membrane proteins in different lipid environments. The fundamental findings have theoretical and practical implications beyond the study of EGFR to all membrane signalling proteins. The evidence supporting the conclusions is compelling, based on the use of a nanodisk system to study membrane proteins in vitro, combined with state-of-the-art single-molecule FRET. The work will be of broad interest to cell biologists and biochemists.
Abstract
Cell surface receptors transmit information across the plasma membrane to connect the extracellular environment to intracellular function. While the structures and interactions of the receptors have been long established as mediators of signaling, increasing evidence suggests that the membrane itself plays an active role in both suppressing and enhancing signaling. Identifying and investigating this contribution has been challenging owing to the complex composition of the plasma membrane.
We used cell-free expression to incorporate the epidermal growth factor receptor (EGFR) into nanodiscs with defined membrane compositions and characterized ligand-induced transmembrane conformational response and interactions with signaling partners using single-molecule and ensemble fluorescence assays. We observed that both the transmembrane conformational response and interactions with signaling partners are strongly lipid dependent, consistent with previous observations of electrostatic interactions between the anionic lipids and conserved basic residues near the membrane adjacent domain.
Strikingly, the active conformation of EGFR and high levels of ATP binding were maintained regardless of ligand binding with high anionic lipid content typical of cancer cells, where EGFR signaling is enhanced.
In contrast, the conformational response was suppressed in the presence of cholesterol, providing a mechanism for its known inhibitory effect on EGFR signaling.
Our findings introduce a model of EGFR signaling in which the lipid environment can override ligand control, providing a biophysical basis for both robust EGFR activity in healthy cells and aberrant activity under pathological conditions. The membrane-adjacent protein sequence, likely responsible for the lipid dependence, is conserved among receptor tyrosine kinases, suggesting that active regulation by the plasma membrane may be a general feature of this important class of proteins."
Fig. 2 Membrane composition influences EGFR function through ATP binding.
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