In This Issue

Spotlight on membranes

Understanding the behavior of membranes, which are composed of several hundred lipid species, is a daunting and complex problem. To begin with, we don't know the fundamental physical chemistry of lipid and protein mixing in a bilayer. Feigenson discusses the beginnings of our understanding of real membranes through the recent development of phase diagrams of three-component systems, which reveal rich phase behavior [Commentary, p. 560 ]. The implications on the controversy surrounding cholesterol-rich 'lipid raft' domains are also discussed.

In another Commentary, Zimmerberg and Gawrisch discuss the chemical nature of lipids and how it determines their role in lipid-protein interactions and membrane function [Commentary, p. 564 ]. As accurate models of true membranes are currently an unrealistic goal, the authors outline their recommendation of combining the knowledge gained from the historical and relatively simplistic practice of treating the membrane as a continuous medium with an account of the chemical and biophysical interactions of specific amino acid residues and lipids.

Given these roles of lipids in maintaining the diversity of membranes and membrane functions, lipid metabolism and organization becomes more important and meaningful. A Perspective by Ile, Schaaf and Bankaitis explores the role of phosphatidylinositol transfer proteins (PITPs) in the movement of lipids from one leaflet of a membrane to the other and how this comes into play in maintaining membrane diversity during synthesis, diffusion and membrane traffic [Perspective, p. 576 ]. The authors propose that PITPs join phospholipids, lipid biosynthetic enzymes and specific lipid binding components to form “nanoreactor” machines that regulate lipid metabolism and signaling.

Beyond the lipids themselves, biological membranes have thousands of proteins associated with them. The hydrophobic moieties provided by fatty acylation and prenylation in their most elementary role allow this association with membranes. Additional complexity is added by the ability of lipid modifications to regulate protein function. Resh reviews the most recent descriptions of the substrates and enzymes involved in lipidation, as well as the roles of individual lipids in regulating membrane targeting, trafficking and signaling [Review, p. 584 ]. MB

Monopolizing mitotic spindles

Cell division requires the precise coordination of numerous processes, including the assembly of the bipolar mitotic spindle, which orchestrates chromosomal segregation. Biochemical and RNA interference knockdown studies have revealed important components of this machinery, including Polo-like kinases (Plks), a class of serine/threonine kinases, which have been implicated as regulators of mitotic progression. Two studies now identify small-molecule Plk inhibitors and use them to understand the roles of Plks in assembly and maintenance of the mitotic spindle. McInnes et al. used kinase homology modeling and in silico screening to identify a class of Plk inhibitors, called cyclapolins, based on a benzthiazole N-oxide scaffold. Cyclapolin 1 was shown to be a selective Plk1 inhibitor, as it caused shortening of the mitotic spindle, and in some cases formation of a monopolar spindle. In a separate study, Peters et al. explored whether a focused compound library could be used to identify small-molecule inhibitors capable of inducing diverse cell-division phenotypes. A cell-based screen of a library of 100 diaminopyrimidines produced 22 compounds that perturbed mitosis. One of the active compounds, DAP-81, is a known inhibitor of Plk1, and the authors showed that it inhibits Plk activity in cells at concentrations that produced monopolar spindles. Taken together, these two studies provide new insight into the roles of Plks during spindle assembly and maintenance and demonstrate the utility of small-molecule probes for understanding cell-division processes. [Articles, p. 608 , 618 ] TLS

NO opens doors

S-nitrosylation involves the addition of a nitrogen monoxide (NO) group to a cysteine thiol and is thought to be important for transmitting cellular signals. NO signals are coordinated with the signals from Ca²⁺ entering through transient receptor potential (TRP) cation channels. These diverse channels are important for many sensory systems including recognition of thermal changes and pain, and mechanical cell stretching. Yoshida et al. now report that there is an additional connection between NO and Ca²⁺ signals: the S-nitrosylation of TRP channels. The authors show that Ca²⁺ flux through both TRPC and TRPV channel subtypes is activated by S-nitrosylation or oxidative modifications of specific cysteine residues on these channels. These results suggest that S-nitrosylation regulates cellular Ca²⁺ flux and may be important for responding to and mitigating cellular stress, such as that encountered during heat or pain sensations. [Articles, p. 596 ; News & Views, p. 570 ] MB

The importance of being glutamate

Ion channels must be regulated to allow ion transport in a controlled fashion, yet the molecular mechanisms by which this happens are not known. Now Hong et al. demonstrate that the outer-membrane protein OmpA is regulated by the alternate pairing of a glutamate with either a neighboring arginine (channel closed) or lysine (channel open). They further demonstrate, for the first time, that the channel has physiological relevance—it facilitates cell growth under osmotic stress. The strength of the glutamate-arginine salt bridge is surprisingly strong, which suggests that this may be an overlooked interaction in gating mechanisms in general. [Articles, p. 627 ; News & Views, p. 572 ] CG

In This Issue written by Mirella Bucci, Catherine Goodman and Terry L. Sheppard