Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Three-Part Handoff Delivers Proteins to Membrane Surface

26.08.2011
The delivery system for an important class of proteins in the cell membrane can be fully replicated with a mere three components, according to a new study.

Tail-anchored proteins, the molecular machines that make up approximately five percent of the membrane proteins in a cell, are known to have their own special pathway for trafficking to the membrane after construction. New research from the University of Chicago and the National Institutes of Health blending structural and functional experiments finds that these proteins can be delivered to the membrane via a simple three-part system.

This deeper understanding of the tail-anchored protein pathway could have significance for the development of new drugs and bioengineering methods. Researchers studying how other types of proteins are delivered to the membrane may also benefit from comparison with this specialized pathway as it is further manipulated and dissected.

"What we are really excited about is the prospect of having a completely defined, completely synthetic controlled system," said Robert Keenan, PhD, Assistant Professor of Biochemistry and Molecular Biology at the University of Chicago. "Now we can really start asking detailed mechanistic questions."

A team of six scientists from the University of Chicago and the National Institute of Child Health and Human Development, led by Keenan and Ramanujan Hegde, MD, Ph.D., published the findings on Wednesday in the journal Nature.

Proteins are put together by ribosomes, which read DNA instructions and link amino acids together into their final form. But many proteins must be delivered from the ribosome to the endoplasmic reticulum (ER), where they are packaged and sent to their final destination.

The majority of membrane proteins navigate this route by using the "co-translational pathway," where the ribosome builds the protein directly into the ER membrane. But tail-anchored (TA) proteins, so named because only a single, small stretch at the "tail" end of the protein sits in the membrane, are known to use a different delivery system.

"TA proteins play all sort of important roles in a variety of different cellular functions," Keenan said. "If you screw this pathway up, bad things will happen. At that level they are just fundamentally important."

The first component from this new system was identified in 2007 by Hegde (now at the MRC Laboratory of Molecular biology in Cambridge, England). That protein, called Get3 in yeast, was subsequently discovered to interact with two proteins called Get1 and Get2. But researchers hadn't yet determined how these components worked, and whether these three alone could account for TA protein targeting.

Leading the collaboration between Keenan and Hegde's laboratories, co-first authors Agnieszka Mateja of the University of Chicago and Malaiyalam Mariappan of the National Institute of Child Health and Human Development created a synthetic system containing only Get1, Get2, Get3, and a TA protein substrate. The substrate was successfully delivered to the endoplasmic reticulum membrane, confirming that the three-part system was sufficient for trafficking.

The scientists then deleted or modified specific pieces of the Get proteins to see how these elements work together to move a tail-anchored protein to its proper position in the cell membrane. The new model of the pathway includes both Dr. Octopus-like hooks, a handoff between two closely partnered proteins, and an elegant system for recycling.

1. A complex of two Get3’s bound to two molecules of ATP form a “groove” of the right size and chemical properties to capture a tail-anchored protein (the "substrate") in the cytosol.

2. Once the substrate is safely nestled in the groove, “hooks” on the end of Get2 grab the complex, and bring it to the membrane. The long, flexible arms of Get2 allow it to function in a way that Keenan jokingly says is “like Dr. Octopus.”

3. Next, Get2 executes a football-style handoff to the adjacent Get1 protein. Binding to Get1 causes the two Get3s to partially “unzip,” wedging open the groove and releasing the tail-anchored substrate for insertion into the membrane.

4. Finally, new ATP molecules bind to Get3 causing it to zip back up into the closed form. This releases it from Get1 so that it can initiate another round of protein delivery in the cytosol.

"We have a minimal system, completely purified, that's only three components plus the substrate," Keenan said. "Now we can basically do whatever we want. We can make mutants or chemical modifications, and then we can reconstitute the system and ask, 'does it work?' And if it doesn't work, we can ask where in this process does it actually fail, and why."

Some steps of the pathway remain incomplete, such as how the tail-anchor of the protein is finally inserted into the membrane after it is released by Get3. But with the purified system, researchers can begin exploring these questions, and comparing the TA protein pathway to the more complex co-translational pathway.

As the delivery systems for proteins of all types are better understood, scientists can then use these systems to create better drugs and manipulate cells for bioengineering purposes. For example, some viruses are thought to exploit protein delivery pathways, and understanding the details of trafficking may suggest new ways of defending cells against infection.

"The more we understand about different targeting pathways, the better our ability to successfully target proteins where we want," Keenan said. "Right now, there's no killer app, but you can imagine a lot of potential uses."

The study, "The mechanism of membrane-associated steps in tail-anchored protein insertion," will be published August 24th online by Nature. In addition to Mariappan, Mateja, Hegde, and Keenan, Malgorzata Dobosz and Elia Bove of the University of Chicago are authors on the study.

Funding for the research was provided by the National Institutes of Health, The Camille and Henry Dreyfus Postdoctoral Program in Environmental Chemistry, and the Edward J. Mallinckrodt, Jr. Foundation.

Robert Mitchum | Newswise Science News
Further information:
http://www.uchospitals.edu

More articles from Life Sciences:

nachricht Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel

nachricht Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Powerful IT security for the car of the future – research alliance develops new approaches

The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.

Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...

Im Focus: Molecular switch will facilitate the development of pioneering electro-optical devices

A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.

The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

In focus: Climate adapted plants

25.05.2018 | Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

 
Latest News

In focus: Climate adapted plants

25.05.2018 | Event News

Flow probes from the 3D printer

25.05.2018 | Machine Engineering

Less is more? Gene switch for healthy aging found

25.05.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>