Modeling cell's messengers

ANN ARBOR, Mich.—Humans have millions of cells to conduct the business of the body. By exchanging chemical signals, cells talk to each other to perform functions like regulating blood pressure, converting food into nutrition and sensing pain or danger.

Along this superhighway of communication, the family of G proteins is one of the most consequential messengers . G proteins have been implicated in the signaling for dozens of metabolic functions including blood pressure, blood clotting, sight and smell. Despite their centrality to the basic systems of life, many aspects of the G proteins' structure and function remain a mystery.

Now, John Tesmer, Life Sciences Institute research associate professor and associate professor in U-M Medical School's Department of Pharmacology, has captured a picture of these messengers in their active state: when they are conveying signals at the cell membrane. The research was published this month in the leading journal Science.

Tesmer's new study, which provides high-resolution models of one G protein involved in blood clot formation, heart disease, and blood pressure, is the first molecular view of how these important proteins can be arranged at the cell membrane. Researchers can now target these protein complexes to try to develop new tools and therapeutic drugs for treating conditions like cardiovascular disease.

Using X-Ray crystallography, Tesmer determined that the atomic structure of a G protein is interacting with an important signaling switch called GRK2. Defects in either the protein or the switch could lead to severe heart development defects. The atomic structure of these multiple molecular complexes are extremely difficult to obtain and this work represents an important step forward for capturing nature in action.

The paper, "Snapshot of Activated G proteins at the Membrane: Structure of the G a q -GRK2-G bg Complex" by Tesmer, appears in the journal Science Dec. 9.

Related links:
Science article
Life Sciences Institute

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The original press release can be found here

[Note: Published in Science, 9 December 2005, Vol. 310. no. 5754, pp. 1686 - 1690, DOI: 10.1126/science.1118890; Valerie M. Tesmer, Takeharu Kawano, Aruna Shankaranarayanan, Tohru Kozasa, John J. G. Tesmer; "Snapshot of Activated G Proteins at the Membrane: The Gq-GRK2-Gß Complex."

Some experiments were performed at Advanced Light Source (Lawrence Berkeley National Laboratory), beamline 8.3.1. Lawrence Berkeley National Laboratory is funded by the U.S. Department of Energy's Office of Science.- lightsources.org]

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