Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


UCSD discovery may provide novel method to generate medically useful proteins


Graphic shows molecular structure of predator protein variants (colors reveal different amino acids) Credit: Jason Miller, UCSD

A team led by UCSD biochemists has discovered the mechanism by which a simple organism can produce 10 trillion varieties of a single protein, a finding that provides a new tool to develop novel drugs.

In the September 18 advance on-line publication of the journal Nature Structural and Molecular Biology, the researchers describe the mechanism by which a virus that infects bacteria—called a bacteriophage, or phage—can generate a kaleidoscope of variants of a particular protein. The paper will appear in print in Nature Structural and Molecular Biology in October.

Since this degree of protein diversity is extremely rare, recreating the process in a test tube could give researchers a new way to generate therapeutic enzymes, vaccines and other medically important proteins.

“This is only the second type of massively variable protein ever discovered,” explained Partho Ghosh, a professor of chemistry and biochemistry at UCSD who headed the research team. “Only antibodies have more variation than this protein in phage. However, the genetic mechanism used by the phage to generate this diversity is completely different from that used by animals to produce antibodies, and has the advantage of giving the protein greater stability.”

“If we can learn from these organisms how to set up a system that churns out proteins with enormous variability, it may be possible to target these new proteins to specific cells to treat disease,” said Stephen McMahon, a former postdoctoral fellow in Ghosh’s lab who conducted much of the research. “This idea has already been picked up by the biotech industry.”

The function of the massively variable phage protein is to tether the phage to the bacteria they infect. The phage “predator” protein fits into a “prey” protein on the bacteria like a three-dimensional puzzle piece. However, the bacteria are constantly changing the proteins on their surface. To keep up with the unpredictable changes in the prey protein, the phage must generate many different predator proteins for at least one to have an acceptable fit.

In their paper, the researchers describe how by altering the amino acids at one or more of just 12 sites on the predator protein, the phage are able to generate 10 trillion proteins, each with the potential to bind to a different prey protein. This variability arises as DNA is being copied into the RNA blueprint for the protein. The sequence of DNA bases at the 12 sites has unique characteristics that cause frequent mistakes to be made in the copying process. As a result, the RNA ends up specifying a different amino acid, and a protein with different structural and chemical properties is created.

Antibodies are another type predator protein that must respond to rapidly evolving prey proteins, because microorganisms are constantly altering proteins on their surfaces to evade the immune system. Unlike the phage protein, antibodies have a complicated loop structure. The size of the loops varies in addition to the amino acid building blocks that constitute the antibody protein. Although this mechanism can generate more than 100 trillion different antibodies, the researchers say replicating it in a test tube would be very challenging because the loops would have the tendency to fold incorrectly.

“Because of its stability, the phage protein makes a better model to create protein diversity in a test tube,” explained Jason Miller, a graduate student in Ghosh’s lab who conducted much of the research. “Our discovery shows that nature has provided at least two completely different methods to generate a huge amount of protein variability, and it opens up a whole new platform for protein development.”

Other contributors to the paper were Jeffrey Lawton, Department of Chemistry, Eastern University; Donald Kerkow, The Scripps Research Institute; Marc Marti-Renom, Eswar Narayanan, and Andrej Sali, Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, University of California, San Francisco; Asher Hodes, and Jeffrey Miller, Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine and the Molecular Biology Institute, University of California, Los Angeles; and Sergei Doulatov, Department of Microbiology and Medical Genetics, University of Toronto.

Stephen McMahon is now at the Centre for Biomolecular Sciences at The University of St. Andrews in Scotland.

This research was supported by a W.M. Keck Distinguished Young Scholars in Medicine Award and a UC Discovery Grant.

Sherry Seethaler | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Make way for the mini flying machines
21.03.2018 | American Chemical Society

nachricht New 4-D printer could reshape the world we live in
21.03.2018 | American Chemical Society

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Alliance „OLED Licht Forum“ – Key partner for OLED lighting solutions

Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.

They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...

Im Focus: Mars' oceans formed early, possibly aided by massive volcanic eruptions

Oceans formed before Tharsis and evolved together, shaping climate history of Mars

A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...

Im Focus: Tiny implants for cells are functional in vivo

For the first time, an interdisciplinary team from the University of Basel has succeeded in integrating artificial organelles into the cells of live zebrafish embryos. This innovative approach using artificial organelles as cellular implants offers new potential in treating a range of diseases, as the authors report in an article published in Nature Communications.

In the cells of higher organisms, organelles such as the nucleus or mitochondria perform a range of complex functions necessary for life. In the networks of...

Im Focus: Locomotion control with photopigments

Researchers from Göttingen University discover additional function of opsins

Animal photoreceptors capture light with photopigments. Researchers from the University of Göttingen have now discovered that these photopigments fulfill an...

Im Focus: Surveying the Arctic: Tracking down carbon particles

Researchers embark on aerial campaign over Northeast Greenland

On 15 March, the AWI research aeroplane Polar 5 will depart for Greenland. Concentrating on the furthest northeast region of the island, an international team...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

Virtual reality conference comes to Reutlingen

19.03.2018 | Event News

Ultrafast Wireless and Chip Design at the DATE Conference in Dresden

16.03.2018 | Event News

International Tinnitus Conference of the Tinnitus Research Initiative in Regensburg

13.03.2018 | Event News

Latest News

New 4-D printer could reshape the world we live in

21.03.2018 | Life Sciences

Alliance „OLED Licht Forum“ – Key partner for OLED lighting solutions

21.03.2018 | Trade Fair News

Physicists made crystal lattice from polaritons

20.03.2018 | Physics and Astronomy

Science & Research
Overview of more VideoLinks >>>