Navigation Links
UCSD discovery may provide novel method to generate medically useful proteins

A team led by University of California, San Diego 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 unpredictab le 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, Department s 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.


'"/>

Source:University of California - San Diego


Related biology news :

1. Protein discovery could unlock the secret to better TB treatment
2. Purdue proves concept of using nano-materials for drug discovery
3. UCSD discovery may help extend life of natural pesticide
4. Leprosy microbes lead scientists to immune discovery
5. Biochemists report discovery of structure of major piece of telomerase; implications for cancer
6. Researchers make surprise discovery that some neurons can transmit three signals at once
7. Important discovery about second most fatal cancer
8. Harmless virus may hold key to more effective HIV drug discovery
9. Fundamental discovery -- Bone fracture
10. Genetic discovery could lead to drought-resistant plants
11. Gene discovery sheds light on causes of rare disease, cancer
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:5/9/2016)... , UAE, May 9, 2016 ... it comes to expanding freedom for high net worth ... Even in today,s globally connected world, there is still ... system could ever duplicate sealing your deal with a ... second passports by taking advantage of citizenship via investment ...
(Date:4/26/2016)... , April 27, 2016 ... the  "Global Multi-modal Biometrics Market 2016-2020"  report to ... ) , The analysts forecast the ... CAGR of 15.49% during the period 2016-2020.  ... number of sectors such as the healthcare, BFSI, ...
(Date:4/13/2016)... physicians supporting Medicaid patients in Central Florida ... telehealth thanks to a new partnership with higi.   ... can routinely track key health measurements, such as blood ... they opt in, share them with IMPOWER clinicians through ... location at no cost. By leveraging this data, IMPOWER ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... ... 23, 2016 , ... Mosio, a leader in clinical research ... Recruitment and Retention Tips.” Partnering with experienced clinical research professionals, Mosio revisits the ... tools, and strategies for clinical researchers. , “The landscape of how patients receive ...
(Date:6/23/2016)... Mass. , June 23, 2016   ... development of novel compounds designed to target cancer ... napabucasin, has been granted Orphan Drug Designation from ... the treatment of gastric cancer, including gastroesophageal junction ... stemness inhibitor designed to inhibit cancer stemness pathways ...
(Date:6/23/2016)... , June 23, 2016 A person commits a ... crime scene to track the criminal down. An ... Food and Drug Administration (FDA) uses DNA evidence to track ... Sound far-fetched? It,s not. The FDA has increasingly ... support investigations of foodborne illnesses. Put as simply as possible, ...
(Date:6/23/2016)... ... June 23, 2016 , ... ... and Mold) microbial test has received AOAC Research Institute approval 061601. , “This ... introduced last year,” stated Bob Salter, Vice President of Regulatory and Industrial Affairs. ...
Breaking Biology Technology: