Daily Archives: January 15, 2017

Study reveals way to design key protein-binding structures

Scientists at the University of Washington in Seattle have deciphered key rules that govern how proteins form pocket-like structures essential to many protein functions.

The discovery makes it possible to design proteins that mimic the actions of naturally occurring proteins as well as to design new proteins, unlike any found in nature, capable of performing entirely new functions.

Illustration of a sample computationally designed protein made of curved beta-sheets and helices. Image credit: UW Institute for Protein Design

“This approach will allow scientists to fine-tune the size and shape of these pockets, or cavities, so that custom-designed proteins can bind to and act on specific molecular targets,” said David Baker, UW professor of biochemistry and director of the UW Institute for Protein Design. He led the research. “This method opens the door to the design of new proteins capable of entirely new functions, including catalyzing reactions not seen in nature, and has many potential applications, including the development of new diagnostic tests and treatments.”

Baker and his colleagues report their findings in the January 13 issue of the journal Science.

A protein is made of chains of amino acids that fold into a compact shape that determines its function. Baker and colleagues studied structures within proteins that form when several chain strands align next to each other to create sheet-like structures, called β-sheets (“beta sheets”). In many natural proteins these sheets bend to form pockets or cavities that bind to target molecules involved in many cellular processes. These target molecules are called “ligands,” and the process by which they are captured in a protein pocket is called “ligand-binding.”

Currently scientists who hope to design a new protein to bind a particular ligand typically try to find a natural protein that has a pocket with a shape similar to what is needed to bind the target ligand molecule.  Using the naturally occurring pocket as a model, they try to alter its structure to bind to the new target.

In many cases, though, it is difficult to find ideal natural models. Those proteins with the desired shapes may not tolerate design modifications, or fail to function in environments other than which they occur naturally.

The UW scientists examined natural protein structures with curved β-sheets to identify key features of amino-acid sequence and orientation within the strands, and the interactions between adjacent strands that govern how β-sheets flex and curve.

“Generally, when β-sheets are uniform, they tend to be relatively flat,” explained the paper’s lead author, Enrique Marcos, a former postdoctoral fellow in Baker’s lab now with the Institute for Research in Biomedicine in Barcelona, Spain. “However, by incorporating breaks in this uniformity, it turns out it is possible to bend the sheet to a desired shape.”

For example, in flat β-sheets, structures in the amino acids called residues tend to alternate from hydrophilic (water-loving) and hydrophobic (water-fearing) as you move down a strand. However, the researchers found that disrupting this alternating pattern by placing two residues of the same type on the same side of the sheet, it was possible to create an elbow-like structure, called a “bulge” where the strand can bend, allowing the sheet to flex.

A second way to break in uniformity that affects the  β-sheet’s shape that the researchers identified, called a “register shift,” occurs when the bonding between adjacent strands terminates, allowing one of the two strands to bend.

By identifying these two factors, the researchers show that it is possible to design and experimentally produce a variety of protein structures with pockets. They also demonstrated that these proteins can be highly stable, which is essential to functioning as ligand-binding sites.

Other members of the Baker lab team that work on the study are Benjamin Basanta, Tamuka M. Chidyausiku, Gustav Oberdorfer, Daniel-Adriano Silva and Jiayi Dou. Funding support came from the Howard Hughes Medical Institute, the Defense Threat Reduction Agency (HDTRA 1-11-1-0041), a Marie Curie International Outgoing Fellowship (FP7-PEOPLE-2011-IOF 298976), and the Community Outreach Activity of the National Institute of General Medical Sciences Protein Structure Initiative (U54 GM094597)

Source: University of Washington


Three Ways to Be a Winner in the Game of Evolution

A new study by University of Arizona biologists helps explain why different groups of animals differ dramatically in their number of species, and how this is related to differences in their body forms and ways of life.

For millennia, humans have marveled at the seemingly boundless variety and diversity of animals inhabiting the Earth. So far, biologists have described and catalogued about 1.5 million animal species, a number that many think might be eclipsed by the number of species still awaiting discovery.

Jellyfish, polyps and the like belong to a phylum called Cnidaria, one of about 30 major groups that make up the animal kingdom

All animal species are divided among roughly 30 phyla, but these phyla differ dramatically in how many species they contain, from a single species to more than 1.2 million in the case of insects and their kin. Animals have incredible variation in their body shapes and ways of life, including the plantlike, immobile marine sponges that lack heads, eyes, limbs and complex organs, parasitic worms that live inside other organisms (nematodes, platyhelminths), and phyla with eyes, skeletons, limbs and complex organs that dominate the land in terms of species numbers (arthropods) and body size (chordates).

Amid this dazzling array of life forms, one question has remained as elusive as it is obvious: Why is it that some groups on the evolutionary tree of animals have branched into a dizzying thicket of species while others split into a mere handful and called it a day?

From the beginnings of their discipline, biologists have tried to find and understand the patterns underlying species diversity. In other words, what is the recipe that allows a phylum to diversify into many species, or, in the words of evolutionary biologists, to be “successful”? A fundamental but unresolved problem is whether the basic biology of these phyla is related to their species numbers. For example, does having a head, limbs and eyes allow some groups to be more successful and thus have greater species numbers?

In the new study, Tereza Jezkova and John Wiens, both in the University of Arizona’s Department of Ecology and Evolutionary Biology, have helped resolve this problem. They assembled a database of 18 traits, including traits related to anatomy, reproduction and ecology. They then tested how each trait was related to the number of species in each phylum, and how quickly species in each phylum multiplied over time (diversification). The results are published in the journal American Naturalist.

Jezkova and Wiens found that just three traits explained most variation in diversification and species numbers among phyla: the most successful phyla have a skeleton (either internal or external), live on land (instead of in the ocean) and parasitize other organisms. Other traits, including those that might seem more dramatic, had surprisingly little impact on diversification and species numbers: Evolutionary accomplishments such as having a head, limbs and complex organ systems for circulation and digestion don’t seem to be primary accessories in the evolutionary “dress for success.”

“Parasitism isn’t correlated with any of the other traits, so it seems to have a strong effect on its own,” Wiens said.

He explained that when a host species splits into two species, it takes its parasite population(s) with it.

“You can have a number of parasite species living inside the same host,” he said. “For example, there could be 10 species of nematodes in one host species, and if that host species splits into two, there are 20 species of nematodes. So that really multiplies the diversity.”

The researchers used a statistical method called multiple regression analysis to tease out whether a trait such as parasitic lifestyle is a likely driver of species diversification.

“We tested all these unique traits individually,” Wiens explained. “For example, having a head, having eyes, where the species in a phylum tend to live, whether they reproduce sexually or asexually, whether they undergo metamorphosis or not. And from that we picked six traits that each had a strong effect on their own. We then fed those six traits into a multiple regression model. And then we asked, ‘What combination of traits explains the most variation without including any unnecessary variables?’ — and from that we could reduce it down to three key variables.”

The authors point out that the analysis does not make any assumptions about the fossil record, which is not a true reflection of past biodiversity, as it does not reveal most soft-bodied animals or traits like a parasitic lifestyle.

“We wanted to know what explains the pattern of diversity in the species we see today,” Wiens said. “Who are the winners, and who are the losers?”

Marine biodiversity is in jeopardy from human activities such as acidification from carbon emissions, posing an existential threat to many marine animals, Wiens said.

“Many unique products of animal evolution live only in the oceans and could easily be lost, so groups that have survived for hundreds of millions of years could disappear in our lifetime, which is terrible,” he said. “Many of the animals’ phyla that are losers in terms of present-day species numbers tend to be in the ocean, and because of human activity, they may go completely extinct.”

The study also suggests that man-made extinction may wage a heavy toll on Earth’s biodiversity because of the effect of secondary extinctions, Wiens explained.

“When a species goes extinct, all its associated species that live in it or on it are likely to go extinct as well,” he said.

Source: University of Arizona

“Mysterious” Non-protein-coding RNAs Play Important Roles In Gene Expression

In cells, DNA is transcribed into RNAs that provide the molecular recipe for cells to make proteins. Most of the genome is transcribed into RNA, but only a small proportion of RNAs are actually from the protein-coding regions of the genome.

“Why are the non-coding regions transcribed at all? Their function has been mysterious,” said Shelley Berger, PhD, a professor of Cell and Developmental Biology and director of the Penn Epigenetics Institute in the Perelman School of Medicine at the University of Pennsylvania.

Enhancer RNAs boost rate of gene expression from protein-coding gene.

Berger and Daniel Bose, PhD, a postdoctoral fellow in her lab, study the regulation of gene expression from enhancers, non–coding regions of the genome more distant from protein-coding regions. Enhancers boost the rate of gene expression from nearby protein-coding genes so a cell can pump out more of a needed protein molecule.  A mysterious subset of non-coding RNAs called enhancer RNAs (eRNAs) are transcribed from enhancer sequences. While these are important for boosting gene expression, how they achieve this has been completely unknown.

Shedding new light on these elusive eRNAs, they showed that CBP, an enzyme that activates transcription from enhancers, binds directly to eRNAs. This simple act controls patterns of gene expression in organisms by regulating acetylation, a chemical mark that directs DNA tightly packed in the nucleus of cells to loosen to promote transcription. Their findings are published this week in Cell.

“The cells in our bodies share the same genes and DNA sequences, and differ only in how these genes are expressed,” Bose said. “Enhancers and eRNAs are critical for this process. Our work shows an exciting new way that eRNAs produce these different patterns of gene expression. We asked if eRNAs work directly with CBP, and found that they do.”

Source: University of Pennsylvania

Hubble Gazes Into a Black Hole of Puzzling Lightness

The beautiful spiral galaxy visible in the center of the image is known as RX J1140.1+0307, a galaxy in the Virgo constellation imaged by the NASA/ESA Hubble Space Telescope, and it presents an interesting puzzle. At first glance, this galaxy appears to be a normal spiral galaxy, much like the Milky Way, but first appearances can be deceptive!

The Milky Way galaxy, like most large galaxies, has a supermassive black hole at its center, but some galaxies are centered on lighter, intermediate-mass black holes. RX J1140.1+0307 is such a galaxy — in fact, it is centered on one of the lowest black hole masses known in any luminous galactic core. What puzzles scientists about this particular galaxy is that the calculations don’t add up. With such a relatively low mass for the central black hole, models for the emission from the object cannot explain the observed spectrum. There must be other mechanisms at play in the interactions between the inner and outer parts of the accretion disk surrounding the black hole.

Source: NASA

Catching Cassini’s call

Above Saturn

This week, ESA deep-space radio dishes on two continents are listening for signals from the international Cassini spacecraft, now on its final tour of Saturn.

ESA’s sensitive tracking antennas at New Norcia, Western Australia, and Malargüe, Argentina, are being called in to help with crucial observations during Cassini’s last months in orbit, dubbed the ‘Grand Finale’.

The Cassini–Huygens mission is one of the most successful exploration endeavours ever.

Launched in October 1997, the Cassini orbiter delivered Europe’s Huygens probe to the surface of Saturn’s mysterious moon Titan in 2005, just a few months after becoming the first spacecraft to enter orbit around the giant gas planet.

In addition to Huygens’ historic delivery 12 years ago on 14 January, Cassini has returned a wealth of information from Saturn’s system, including images and other data from the massive planet, its multiple moons and its hauntingly beautiful system of rings.

Huygens landing on Titan

Now running low on fuel, Cassini will be commanded to dive into Saturn’s upper atmosphere on 15 September, where it will burn up like a meteor.

As part of its final ambitious observing plan, the craft began last month making a series of 20 orbits, arcing high above the planet’s north pole then diving down, skimming the narrow F-ring at the edge of the main rings.

Then, starting in April, Cassini will leap over the rings to begin its final series of 22 daring dives, taking it between the planet and the inner edge of the rings.

Between December 2016 and July 2017, ESA’ ground stations will work with NASA’s Deep Space Network to record radio signals transmitted by Cassini across 1.6 billion km, helping scientists to study Saturn’s atmosphere and its enigmatic rings, bringing us closer to understanding its origins.

New Norcia tracking station

They will record signals transmitted from Cassini that have crossed or bounced off Saturn’s atmosphere or rings. Variations in the strength and frequency contain valuable information on the composition, state and structure of whatever they have passed through.

In addition, tiny wobbles in Cassini’s orbit due to the varying pull of gravity can be teased from the signals, helping to build our understanding of the planet’s interior.

First passes

The first three recording passes involving ESA stations were conducted in December, followed by two more on 3 and 10 January. Twenty more deep-space link-ups are scheduled.

“For the first few months of 2017, we’re mostly recording signals that will transit through the ring system or the atmosphere,” says Daniel Firre, the service manager at ESA’s mission control centre in Darmstadt, Germany.

“After April, as Cassini’s orbit gets lower, we’ll switch to recording signals to be used for gravity analysis.”

The recordings – some batches comprising up to 25 GB – are passed to the Cassini radio science team for analysis.

“The ESA stations are helping to acquire extremely important radio science data from Cassini, highlighting how interagency cooperation can make planetary missions even more valuable,” notes Aseel Anabtawi, from the radio science group at NASA’s Jet Propulsion Laboratory.

Some recording contacts between Cassini and Earth will last over 10 hours, and require technically complex handovers of the signal from an ESA to a NASA station and vice versa. In addition, specialists in Darmstadt must perform very precise frequency calculations for the recording passes.

“Supporting Cassini radio science for the mission’s Grand Finale requires not only teamwork at ESA, but also deep collaboration between the agencies,” says ESA’s Thomas Beck, responsible for ground station services.

“This is part of our continuing mutual support that is yielding real scientific and engineering value.”

Source: ESA