Nav: Home

Scientists create complex transmembrane proteins from scratch

March 01, 2018

It is now possible to create complex, custom-designed transmembrane proteins from scratch, scientists report this week. The advance, led by molecular engineers at the University of Washington Institute for Protein Design, will enable researchers to create transmembrane proteins not found in nature to perform specific tasks.

In the living world, transmembrane proteins are found embedded in the membrane of all cells and cellular organelles. They are essential for them to function normally. For example, many naturally occurring transmembrane proteins act as gateways for the movement of specific substances across a biological membrane. Some transmembrane proteins receive or transmit cell signals. Because of such roles, many drugs are designed to target transmembrane proteins and alter their function.

"Our results pave the way for the design of multispan membrane proteins that could mimic proteins found in nature or have entirely novel structure, function and uses," said David Baker, a University of Washington School of Medicine professor biochemistry and director of the UW Institute of Protein Design who led the project. The research is reported in the March 1 issue of the journal Science. Peilong Lu, a senior fellow in the Baker lab, is the paper's lead author.

But understanding how transmembrane proteins are put together and how they work has proved challenging. Because they act while embedded within the cellular membrane, transmembrane proteins have proven to be more difficult to study than proteins that operate in the watery solution that make up the cells' cytoplasm or in the extracellular fluid.

In the new study, Lu and his coworkers used a computer program, developed in the Baker lab and called Rosetta, that can predict the structure a protein will fold into after it has been synthesized. The architecture of a protein is crucial because a protein's structure determines its function.

A protein's shape forms from complex interactions between the amino acids that make up the protein chain and between the amino acids and the surrounding environment. Ultimately, the protein assumes the shape that best balances out all these factors so that the protein achieves the lowest possible energy state.

The Rosetta program used by Lu and his colleagues can predict the structure of a protein by taking into account these interactions and calculating the lowest overall energy state. It is not unusual for the program to create tens of thousands of model structures for an amino acid sequence and then identify the ones with lowest energy state. The resulting models have been shown to accurately represent the structure the sequence will likely assume in nature.

Determining the structure of transmembrane proteins is difficult because portions of transmembrane proteins must pass though the membrane's interior, which is made of oily fats called lipids.

In aqueous fluids, amino acid residues that have polar sidechains - components that can have a charge under certain physiological conditions or that participate in hydrogen bonding -- tend to be located on the surface of the protein where they can interact with water, which has negatively and positively side charges to its molecule. As a result, polar residues on proteins are called hydrophilic, or "water-loving."

Non-polar residues, on the other hand, tend to be found packed within the protein core away from the polar aqueous fluid. Such residues are called hydrophobic or "water-fearing." As a result, the interaction between the water-loving and water-fearing residues of the protein and the surrounding watery fluids helps drive protein folding and stabilizes the protein's final structure.

In membranes, however, protein folding is more complicated because the lipid interior of the membrane is non-polar, that is, it has no separation of electrical charges. This means to be stable the protein must place nonpolar, water-fearing residues on its surface, and pack its polar, water-loving residues inside. Then it must find a way to stabilize its structure by creating bonds between the hydrophilic residues within its core.

The key to solving the problem, says Lu, was to apply a method developed by Baker lab to design proteins so that the polar, hydrophilic residues fit in such a way that enough would form polar-polar interactions that can tie the protein together from within.

"Putting together these 'buried hydrogen bond networks' was like putting together a jig-saw puzzle," Baker said.

With this approach, Lu and his colleagues were able to manufacture the designed transmembrane proteins inside bacteria and mammalian cells by using as many as 215 amino acids. The resulting proteins proved to be highly thermally stable and able to correctly orient themselves on the membrane. Like naturally occurring transmembrane proteins, the proteins are multipass, meaning they traverse the membrane several times, and assemble into stable multi-protein complexes, such as dimers, trimers and tetramers.

"We have shown that it is now possible to accurately design complex, multipass transmembrane proteins that can be expressed in cells. This will make it possible for researchers to design transmembrane proteins with entirely novel structures and functions," said Lu.
-end-


University of Washington Health Sciences/UW Medicine

Related Amino Acids Articles:

Alzheimer's: Can an amino acid help to restore memories?
Scientists at the Laboratoire des Maladies Neurodégénératives (CNRS/CEA/Université Paris-Saclay) and the Neurocentre Magendie (INSERM/Université de Bordeaux) have just shown that a metabolic pathway plays a determining role in Alzheimer's disease's memory problems.
New study indicates amino acid may be useful in treating ALS
A naturally occurring amino acid is gaining attention as a possible treatment for ALS following a new study published in the Journal of Neuropathology & Experimental Neurology.
Breaking up amino acids with radiation
A new experimental and theoretical study published in EPJ D has shown how the ions formed when electrons collide with one amino acid, glutamine, differ according to the energy of the colliding electrons.
To make amino acids, just add electricity
By finding the right combination of abundantly available starting materials and catalyst, Kyushu University researchers were able to synthesize amino acids with high efficiency through a reaction driven by electricity.
Nanopores can identify the amino acids in proteins, the first step to sequencing
While DNA sequencing is a useful tool for determining what's going on in a cell or a person's body, it only tells part of the story.
Differentiating amino acids
Researchers develop the foundation for direct sequencing of individual proteins.
Simulating amino acid starvation may improve dengue vaccines
In a new paper in Science Signaling, researchers at the University of Hyderabad in India and the Cornell University College of Veterinary Medicine show that a plant-based compound called halofuginone improves the immune response to a potential vaccine against dengue virus.
CoP-electrocatalytic reduction of nitroarenes: a controllable way to azoxy-, azo- and amino-aromatic
The development of a green, efficient and highly controllable manner to azoxy-, azo- and amino-aromatics from nitro-reduction is extremely desirable both from academic and industrial points of view.
Origin of life insight: peptides can form without amino acids
Peptides, one of the fundamental building blocks of life, can be formed from the primitive precursors of amino acids under conditions similar to those expected on the primordial Earth, finds a new UCL study published in Nature.
Researchers develop fast, efficient way to build amino acid chains
Researchers report that they have developed a faster, easier and cheaper method for making new amino acid chains -- the polypeptide building blocks that are used in drug development and industry -- than was previously available.
More Amino Acids News and Amino Acids Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Teaching For Better Humans 2.0
More than test scores or good grades–what do kids need for the future? This hour, TED speakers explore how to help children grow into better humans, both during and after this time of crisis. Guests include educators Richard Culatta and Liz Kleinrock, psychologist Thomas Curran, and writer Jacqueline Woodson.
Now Playing: Science for the People

#556 The Power of Friendship
It's 2020 and times are tough. Maybe some of us are learning about social distancing the hard way. Maybe we just are all a little anxious. No matter what, we could probably use a friend. But what is a friend, exactly? And why do we need them so much? This week host Bethany Brookshire speaks with Lydia Denworth, author of the new book "Friendship: The Evolution, Biology, and Extraordinary Power of Life's Fundamental Bond". This episode is hosted by Bethany Brookshire, science writer from Science News.
Now Playing: Radiolab

Space
One of the most consistent questions we get at the show is from parents who want to know which episodes are kid-friendly and which aren't. So today, we're releasing a separate feed, Radiolab for Kids. To kick it off, we're rerunning an all-time favorite episode: Space. In the 60's, space exploration was an American obsession. This hour, we chart the path from romance to increasing cynicism. We begin with Ann Druyan, widow of Carl Sagan, with a story about the Voyager expedition, true love, and a golden record that travels through space. And astrophysicist Neil de Grasse Tyson explains the Coepernican Principle, and just how insignificant we are. Support Radiolab today at Radiolab.org/donate.