SEPTEMBER 1999 PRESS RELEASE

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Research paper p. 878 Research news & views p. 852

Yeast screen hits the G spot

The human body uses specialized molecules called G proteins to relay sensory messages from receptors on the cell surface to the interior. Many of these G-protein coupled receptors (GPCRs) are important therapeutically (almost half of all clinically used drugs target GPCRs), but many of the human proteins involved in modulating function of the G proteins themselves remain unidentified. Now, scientists have created a yeast strain that enables modulators of human G proteins to be identified rapidly and with great sensitivity. Using their screen, they have isolated four human proteins that can stimulate human G protein activity, confirming three of them as bonafide regulators. Screens based on this assay could ultimately enable the identification of drugs that inhibit human G proteins.

To create their yeast screen, Emir Duzic and his colleagues first had to disable the existing pheromone response pathway in yeast. They did this by deleting the genes for the pheromone receptor, the yeast G protein alpha subunit, the Far1p protein (which arrests yeast growth when stimulated by GPCRs), and the His3p protein (which allows growth on the amino acid histidine). They then engineered back into this yeast strain genes encoding part of the yeast G alpha subunit fused to the human G protein alpha subunit and the Fus1p protein (which is pheromone/GPCR inducible) fused to His3p. By plating this yeast strain on a nutritional medium that lacks histidine, they hoped to identify human G protein activators by their ability to confer growth to the modified cells. Sure enough, when they transformed the engineered yeast with a library of human DNA sequences to look for G-protein activators, they identified twenty colonies, analysis of which revealed four different "activator" pro! teins. The approach used by these workers should be applicable to the study of a long list of human genes that have yeast counterparts. What's more, it should eventually be possible to engineer the yeast cell to study important human proteins that have no counterparts in yeast.

Contact (Author)
Emir Duzic
Cadus Pharmaceutical Corporation
777 Old Saw Mill River Road
Tarrytown, NY 10591-6705 USA
Tel: 914-467-6200
Fax: 914-345-3565
Email: eduzic@cadus.com

Contact (Research News & Views)
Robert Frederickson
Research Editor
Nature Biotechnology
Tel: 212 726 9289
Fax: 212 696 9635
r.frederickson@natureny.com

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