Scientists show protein-making machinery can switch gears with a small structural change process

Nov 15, 2012

For the past several years, Min Guo, an assistant professor at The Scripps Research Institute, has focused on the intricate actions of an ancient family of catalytic enzymes that play a key role in translation, the process of producing proteins.

These complex enzymes are a group of fundamental molecules that make for . Present in every cell, these enzymes—known as aminoacyl- synthetases (tRNA synthetases)—select the proper amino acid and assign them to transfer RNAs to make a protein in the . As an essential step of determining the , tRNA synthetases have been around for billions of years.

However, this essential part of the protein-making machine did not stop evolving. Now, in a new study published online ahead of print on November 15, 2012, by the journal Molecular Cell, Guo, Ehud Razin of The Institute for Medical Research Israel-Canada, and a large team of have shown that this can actually also work in another fundamental process in humans. In this case, the enzyme activates a process that creates a copy of RNA from DNA—transcription, which is the first step leading to . All this takes is a single () at a specific site on the enzyme, which then triggers a cascade of structure changes, freeing the enzyme from translation to another role regulating transcription.

"If you think about the structural changes that occur in the synthetase we looked at in the study, it's very much like the movie Transformers," Guo said. "It's a machine that changes structure and turns into another machine that can accomplish a completely different task—like from a car to a giant robot. This is the first time anyone has been able to show how you can change the function of this enzyme from a mechanistic perspective, to know exactly how that works."

This newly discovered ability has large implications for our understanding of , including allergies, and cancer, Guo said. He notes the unusual transformation of tRNA synthetases was initially discovered in mast cells, which are the body's first line of defense against pathogens such as bacteria and viruses. To recognize pathogens and other signs of infection, mast cells are dispersed throughout most tissues, but are crucially located at the body's interfaces with the environment, such as the skin and mucosae. Activation of mast cells is a key step in initiating allergies, in which activated mast cells secrete preformed mediators, such as histamine, and synthesize new mediators that augment the allergic response. It turns out that mast cells mobilize the tRNA synthetases to participate in transcriptional regulation and carry along this entire signal cascade, within minutes.

"This shows how a housekeeping machine can be re-shaped for a regulatory response," Guo said, "something that is only now starting to get noticed."

Recent research has also shown that the transformed synthetase in the new study also increases metastasis in breast cancer cells.

"By designing a way to prevent this synthetase transformation, you could potentially limit metastasis," Guo said. "But you have to know the mechanism before you can design something to alter it. This new study gives us a basic framework that shows how this transformation works."

The first authors of the study, "Structural Switch of Lysyl-tRNA Synthetase between Translation and Transcription," are Yifat Ofir-Birin of The Institute for Medical Research Israel-Canada and Pengfei Fang of TSRI. In addition to Guo, Razin, Ofir-Birin, and Fang, other authors include Steven P. Bennett, Jing Wang, Ryan Shapiro, Jorge Pozo, Paul Schimmel and Xiang-Lei Yang of TSRI (Sharpiro and Schimmel are also affilitated with the Skaggs Institute for Chemical Biology at TSRI); Inbal Rachmin, Jing Song, and Arie Dagan of The Institute for Medical Research Israel-Canada; Hui-Min Zhang and Alan G. Marshall of Florida State University; Sunghoon Kim of Seoul National University; and Hovav Nechushtan of the Hadassah Medical Center, Israel.

"This study required team work, as it spanned the boundaries of different biological fields, including cell biology, structural biology, immunity and cancer," Guo said. "This and future work is made possible by the close collaborations among scientists around the world."

Explore further: Two-armed control of ATR, a master regulator of the DNA damage checkpoint

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kevinrtrs
1 / 5 (6) Nov 17, 2012
As an essential step of determining the genetic code, tRNA synthetases have been around for billions of years.

The question needs to be asked - how do they know that it's been around for billions of years?

There is no documented evidence that anyone observed these "synthetases" even a million, let alone billions of years ago.

There is no historical evidence within any fossil that can support the claim that these things existed and remained so for billions of years. Such organic matter deteriorates far too quickly to remain available after billions of years for examination here in the present.

So this statement begs the question: How do they really know?

The obvious point here is that this is simple, sheer, unadulterated speculation based on evolutionary assumptions.
Period.
kevinrtrs
1 / 5 (6) Nov 17, 2012
This is the first time anyone has been able to show how you can change the function of this enzyme from a mechanistic perspective, to know exactly how that works

This is ALL that has been accomplished. ANything related to the evolutionary origins of the synthethases has absolutely nothing to do with the end result.
It cannot influence it other than being any assumption used to interpret how it might have existed and changed over supposed billions of years. One might as well throw it out the window and the result will still stand, be valid and useful in the here and now. That is the real science in this research.

The statement regarding origins is simply chaff blown in the wind.
jsdarkdestruction
5 / 5 (2) Nov 17, 2012
Wow kevin! you are right, the fact you dont understand something means the world is 6000 yrs old as dictated in your storybook. youve made a believer out of me! *sarcasm*
Torbjorn_Larsson_OM
5 / 5 (3) Nov 18, 2012
Creationists shouldn't comment on science, it is hilarious.

No, we don't need to ask about basic biology that is well known and accepted. Indeed, modern genome sequencing observes all the way back to the beginnings of the RNA/protein cell ~ 4 billion years ago.

Nothing of that discussion has to do with the new research. On the contrary, these results tests the basic biology yet again.

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