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Supersensitive phospholipid sensing

Actin tails are induced by N-WASP (left), which is even more active with extra lysines in its B motif (right). LIM/ELSEVIER

Alysine-laden sensor makes an actin regulator ultrasensitive to phospholipid levels, according to Venizelos Papayannopoulos, Wendell Lim (University of California, San Francisco, CA), and colleagues.

Phospholipids, particularly PIP₂, are activators of N-WASP—an Arp2/3 regulator that turns on actin polymerization. None of the common PIP-binding domains (e.g., Pleckstrin Homology or Phox domains) are found in N-WASP. Instead, a region of 10 basic residues (the B motif) binds to the phospholipids. The new research reveals that this conglomerate of positive charges turns N-WASP into an all-or-nothing switch in response to changing PIP₂ density.

At 10% PIP₂, N-WASP bound tenfold more strongly to vesicles than it did at 2% PIP₂. Even sharper effects from lipid density were seen in actin polymerization assays. Cholesterol, which recruits PIP₂ to lipid rafts, lowered the activation threshold, suggesting that local density, not overall concentration, of the phospholipid is key. "Polymerization must be spatially precise," says Lim. "Having N-WASP respond to the spatial organization of input molecules adds a high level of precision."

Another activator of N-WASP is Cdc42, which the team found significantly lowered the level of PIP₂ required for N-WASP activity. This ability may allow N-WASP to be turned on without altering cellular PIP₂ levels.

The activation threshold is determined by the number of basic residues in the B motif—more lysines allowed N-WASP to be activated at a lower PIP₂ density. N-WASP with extra lysines also bypassed the usual activation mechanisms (i.e., PI5K activation and PIP₂ synthesis) required for vesicle motility in vivo. Says Lim, "this implies that the native protein threshold is set just above the native density [of PIP₂]," which is several-fold higher than that of other phospholipids. "It's tuned to optimize sensitivity," he says, "but also suppress noise under basal conditions."

Reference:

Papayannopoulos, V., et al. 2005. Mol. Cell. 17:181–191.[CrossRef][Medline]

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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This Article Full Text (PDF, 345K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Social Bookmarking                            What's this?