Monday , August 2 2021

Enter information in the cell

Enter information in the cell

PSI biochemist Volodymyr Korhov (right) and Chao Qi, the first author of the study, prepare a sample for cryo-electron microscopy. Yours sincerely: Paul Sheerre Institute / Mahir Jambbegovic

Researchers at the Paul Shcherre Institute (PSI) have clarified an important part of the signaling pathway that transmits information through the cell membrane to the inside of the cell.

The inside of all living cells is separated from the outer world by membranes. These membranes keep the cells intact and protect them from negative influences. But they also act as a barrier to nutrients and information. For this reason, cell membranes contain mechanisms that allow selective access to the desired substances or transmit information from external signals in the cell.

An important mammalian signaling pathway consists of three components: The first is a receptor that recognizes the signal and is activated by it. The second is the so-called G protein that binds to the activated receptor and transmits the signal to one or more effector proteins. In this case, the effector is adenylyl cyclase, the third component of the signal chain. This protein is activated by a G protein subunit and produces a secondary messenger called cyclic AMP (cAMP) in a biochemical reaction.

cAMP causes different reactions in the cell; for example, it increases the permeability of the membrane to calcium in the heart cells, which results in an increase in the rate of heart rhythm.

Researchers at the Paul Scherer Institute in Villegen, Switzerland, have now explored a special type of adenylyl cyclase using electron microscopy and produced the most detailed image of this type of membrane protein.

Enter information in the cell

The inside of the cell is protected from external influences by the cell membrane. In order to transmit information in the cell transmitted by an envoy (H), there are special signaling paths. A: The messenger binds to the receptor in the membrane and activates it (illustrated here by the color change). In turn, the receptor activates G protein. B: This alpha subunit is secreted and binds to the last part of the signal pathway, a protein called adenylyl cyclase. This transforms ATP – which stores energy for the cell – into the so-called cyclic AMP (cAMP), an important secondary messenger in the cell. Sincerely, Paul Scherrer Institute / Markus Fischer

Useful self-restraint

"To understand how signaling pathways work in the cage, we first need to know what the relevant components look like," says Volodymyr Korhov, head of the Transmission of Signal Mechanisms Mechanisms Research Unit at the Department of Biology and Chemistry of the OSH and assistant professor at the Institute of Biochemistry of ETH Zurich. "Our work is an important contribution to clarifying the exact function of adenylyl cyclase in the cAMP signal chain."

"Surprisingly, in determining the structure of adenylyl cyclase associated with the alpha subunit of G protein, we found that the protein seemed to inhibit itself," says Korhov. One part of the protein is responsible for this self-inhibition. This part blocks the active site of the enzyme and prevents over-production of cAMP.

This new look at the molecular structure of adenylyl cyclase provides a much better understanding of how external signals lead to controlled production of the important secondary ambassador cAMP. The cAMP concentration in cells plays an important role in the development of cardiovascular disease, some tumors and type 2 diabetes. "In the future, our new findings could make it possible to identify drugs that inhibit or activate adenylyl cyclase, depending on whether overproduction or lack of cAMP is responsible for the disease, "explains Korhov.

Microscopy at low temperatures

Researchers have achieved their results by cryo-electron microscopy (cryo-EM). This form of transmission electron microscopy works at temperatures below -150 degrees Celsius. The sample to be tested is frozen in liquid ethane while retaining its natural structure. This method, for which the Nobel Prize for Chemistry was awarded in 2017, is increasingly used in the study of biological structures. "It's exciting to get a deep insight into the structure of adenylate cyclase," said Chao Chi, a PhD student at Korhov's Lab and the first author of the study. "The structure of this protein has been elusive for decades since its discovery, and I am glad I was able to clarify this structure with cryo-EM in the course of my doctoral research."

The resolution reached by the IRS researchers in their investigations was 3.4 angstroms. One angstrem is a ten millionth of a millimeter. Isolated atoms have a radius of 0.3-3 angstroms. Researchers have already published their findings in the scientific journal science,

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More information:
"The structure of membrane adenylyl cyclase associated with activated G-stimulating protein" science (2019). … 1126 / science.aav0778

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Paul Sheerre Institute

Importing information into the cage (2019, April 25)
drawn up on 25 April 2019

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