“Crocodile head” sets transcription off
The translation of genetic information into proteins is indispensable for cell function and survival. LMU scientists now reveal the structure of one of the molecular machines involved in the process. Its shape resembles a crocodile’s head.
The proper development of all organisms depends on the regulated expression of the right genes in the right place at the right time, ensuring that each cell can synthesize the proteins required for its particular function. The first step in this process is gene transcription, the synthesis of RNA copies of a defined stretch of the genomic DNA. In higher organisms, the selection of DNA segments for transcription is largely controlled by a large molecular complex consisting of 25-35 proteins, the so-called Mediator complex.
“The Mediator complex transmits activating signals to genes, but it is not yet known how this actually sets gene transcription in motion,” says Professor Patrick Cramer, Director of the Genzentrum at LMU. Now, however, he and his team have determined the three-dimensional structure of one of three modules that make up the Mediator complex.
Bringing the parts together
“We were particularly interested in the structure of one essential element of the Mediator complex, the so-called head module, which is made up of seven subunits,” says Cramer. His research team succeeded in synthesizing all seven subunits in bacterial cells, and could then probe the structure of the assembled module using X-ray crystallographic methods and synchrotron radiation.
The module is shaped like a crocodile’s head, and has several mobile sections, including a “moveable jaw”. The elucidation of its spatial conformation is a milestone in the quest to understand the molecular machinery that mediates transcription initiation at all gene promoters. Commenting on the medical implications of the findings, Cramer says: “Later on, it should be possible to design molecules that perturb Mediator function and inhibit transcription – an approach that could be used to develop new drugs for the treatment of cancers or autoimmune diseases.”
(Nature, Advance Online 31.10.2012) göd