Volume 7 Issue 8, August 2011

Sensors and reporters are among the most exciting tools used in cell biology. Now, they are increasingly used in developmental biology and medicine because they allow us to spy on events in living cells and organisms, including humans, in real time and with high spatial resolution. Herein, we discuss multiple design options for fluorescent sensors and reporters as well as strategies to improve their properties and increase development.

Lambda's 'genetic switch' responds in a dramatic all-or-none fashion to an environmental signal, activating transcription of certain genes as it turns off others. The switch illustrates principal features of many biological regulatory processes.

In response to decreasing Ca²⁺ levels in the endoplasmic reticulum, STIM proteins couple with Orai channels in the plasma membrane, leading to Ca²⁺ influx into the cell. In addition to Ca²⁺-related endoplasmic reticulum stress, STIM proteins are emerging as general stress sensors that react to multiple stress signals to orchestrate Ca²⁺ signaling and homeostasis.

The GTPase switch is a versatile molecular device used by many proteins, such as the small GTPases, to regulate an astounding number of functions. Although the basics of the guanine nucleotide cycle are now well established, the next challenge is to reach an integrated view of how these proteins use it to orchestrate signaling pathways.

Concern over exposure to the radioactive fallout from nuclear power generation is episodic; not surprisingly, it is heightened at present, following the tragedy in Japan. A primary cytotoxin cohort released in such reactor meltdowns consists of isotopes of plutonium (Pu), all radioactive. The most common valence form, Pu(IV), mimics Fe(III) in the transferrin–transferrin receptor pathway; this pathway serves as Pu's 'Trojan horse' through which to enter the body.

A potent and selective inhibitor for the protein lysine methyltransferases G9a and GLP has been discovered. This small molecule serves as a useful probe to decipher the specific role of these enzymes in the development of various diseases.

Peptide agonists of class B G protein–coupled receptors have separate segments for binding and activation. Synthesizing peptidic analogs that can be 'clicked' together allows for rapid optimization of agonist activity—as well as providing some surprises about receptor pharmacology.

Bacteria communicate by sending and receiving chemical cues in a process termed 'quorum sensing'. New research shows how five feedback loops of the Vibrio harveyi quorum sensing cascade ensure signal integration and transmission fidelity, with one loop controlling signal sensitivity by regulating receptor ratios.

D-Ornithine has been used as a supplement under the assumption that it increases production of pyrrolysine-containing proteins, but detailed characterization and investigations of pyrrolysine biosynthesis now demonstrate these modified proteins contain an entirely different amino acid.

The synthetic compound Shield-1 can already be used to protect designed fusion proteins from degradation. The development of a new protein domain that is degraded upon addition of Shield-1 expands the compound's utility in controlling protein function and allows the simultaneous degradation and stabilization of different constructs.

A search through hydrophobic chemical space identifies an adamantane tag that targets dehalogenase fusion proteins for degradation, as demonstrated for both cytosolic and transmembrane proteins; and in zebrafish and mice. This molecule provides a new tool to study protein function with precise control.

Compounds identified from a high-content screen implicate RTK activation as well as GSK-3 inhibition in regulating SMN levels and point to a therapeutic strategy for treating spinal muscular atrophy.

Protein-focused lead-identification strategies may be limited in their ability to identify small molecules that bind to cellular RNAs. Docking small molecules against the structural ensemble substantially improves the docking accuracy of TAR and has led to the identification of six new TAR binders, one of which inhibits HIV-1 replication.

Plutonium (Pu), a radiotoxic element, enters cells via an unknown mechanism. Solution structures and X-ray imaging studies reveal that Pu binds transferrin, and the complex can be taken up by cells via receptor-mediated endocytosis only if iron is contained in transferrin's N-lobe.

Protein lysine methyltransferases modulate the activities of chromatin and non-chromatin proteins by specific methylation of lysine side chains. A large-scale structure-based design approach has yielded a new chemical probe that potently and selectively inhibits G9a and GLP methyltransferases in cells.

Chemical biologists continue to discover how cells translate chemical or physical inputs into biological outputs. This issue includes a collection of articles that delineates the complexity of these switches, highlighting current ideas and future challenges in this research arena.