PRESS RELEASES
Please quote Nature Chemical Biology as the source of these items.
The January 2006 issue of Nature Chemical Biology is available online.
January 2006
Blocking protein secretion
pp 39 - 46A new class of protein secretion inhibitors, which will provide a novel route for studying the basic biology of protein secretion, is reported in the January issue of Nature Chemical Biology. Proteins that will ultimately be secreted from a cell are shuttled through different organelles inside the cell to the plasma membrane. It is difficult to study this intracellular process by biochemical or genetic techniques because it happens relatively quickly. Small-molecules, which are inherently fast acting, can rapidly block specific steps in the process and thus provide an important approach for understanding protein secretion.
Shair, Kirchhausen and colleagues have now identified a class of small molecules, secramines, that inhibit protein movement out of an intracellular organelle involved in protein secretion, called the golgi. Rather than blocking activity, a more typical mechanism of inhibition, secramines acted by preventing the movement of a protein called Cdc42 to the golgi membrane by stabilizing an interaction between Cdc42 and a protein inhibitor.
These chemical inhibitors now provide an important new tool for investigating the role of Cdc42 in protein secretion and may reveal unexpected roles for Cdc42 in other cellular processes.
Activating Smoothened
pp 29 - 30The protein target of a small molecule known to induce stem cell differentiation is reported in a paper in the January issue of Nature Chemical Biology. This molecule, purmorphamine, has been shown to trigger progenitor cell differentiation to osteoblasts, cells that build bones. Purmorphamine was believed to target the Hedgehog signaling pathway, which is involved in many developmental and growth processes in multicellular organisms, including embryonic patterning, tissue regeneration, stem cell renewal and cancer growth. However, the precise target of purmorphamine was not known.
By using a combination of genetics and biochemistry, James Chen and colleagues gradually narrowed down potential targets in the Hedgehog signaling pathway to identify the protein Smoothened as the target. The authors further show that purmorphamine binds directly to a bundle of membrane-spanning helices. However even with this information about the binding site, future studies will be necessary to characterize the precise mechanism for how purmorphamine activates Smoothened.
Because the Hedgehog signaling pathway is involved in many critical developmental processes and diseases, understanding the mechanism of action of this chemical modulator provides a new lead for developing therapeutics for certain cancers, such as brain tumors, and stem cell treatments, such as bone regeneration.
Shining a light on ion channels
pp 47 - 52Ion channels have been engineered so that they can be turned on and off by light, in a manner similar to flipping a switch, according to a paper in the January issue of Nature Chemical Biology. Ion channels – by opening and closing in response to different signals – regulate the flow of ions into and out of cells. Animals do not naturally contain ion channels that respond directly to light. However, controlling channel activity with light would provide a powerful approach for studying ion channel biology because both the timing and location of a light beam can be very precisely controlled.
Glutamate is one of the most common neurotransmitters in the brain, and glutamate receptors are ion channels that open in response to glutamate. Dirk Trauner, Ehud Isacoff and colleagues have attached an agonist – a chemical activator of glutamate receptors – to the outside of the channel. The agonist is linked to the protein by a chemical that stretches out in response to one wavelength of light, and bends into a hairpin in response to a different wavelength of light. The authors show that when this chemical linker is stretched, the channel is closed. But when the linker is bent, the agonist binds to the channel and causes it to open and ions to flow.
These new ‘light-sensitive’ channels can now be used to investigate the neurobiology of glutamate channels, and may also prove valuable for designing nanotechnology devices to be used in biosensing or bioelectronics.
Secramine inhibits Cdc42-dependent functions in cells and Cdc42 activation in vitro
pp 39 - 46Henry E Pelish, Jeffrey R Peterson, Susana B Salvarezza, Enrique Rodriguez-Boulan, Ji-Long Chen, Mark Stamnes, Eric Macia, Yan Feng, Matthew D Shair and Tomas Kirchhausen
Published online: 20 November 2005 | doi 10.1038/nchembio751
Purmorphamine activates the Hedgehog pathway by targeting Smoothened
pp 29 - 30Surajit Sinha and James K Chen
Published online: 20 November 2005 | doi 10.1038/nchembio753
