NEWS OF THE WEEK
PROTEIN GEL MINDS NUCLEAR GATES CELL BIOLOGY: Nuclear pores rely on polymeric meshes to regulate macromolecular traffic
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CELL'S NUCLEAR ENVELOPE is like a building with thousands of screen doors. Galled nuclear pore complexes (NPCs), these gateways control entry to and exit from the nucleus. The basis of this lifesustaining selectivity remains a matter of debate, but new evidence suggests that the central canal of NPCs may be filled with a protein gel bearing molecular motifs key to the pores' selectivity (Science 2006,314,815). NPCs allow free passage of water, ions, and metabolites and other small solutes while carefully controlling the comings and goings of big molecules such as messenger RNA and proteins. The only way molecules larger than about 30 kilodaltons can pass through NPCs is by hitching a ride with nuclear transport receptors (NTRs), a class of proteins with an open invitation to traverse nuclear pore complexes. These shuttling runs, up to 1,000 per second for a single NPC, are perpetrated via interactions between the passenger-carrying NTRs and a common repeating motif in nuclear pore proteins, or nucleoporins, explain Dirk Gorlich, Steffen Frey, and Ralf Richter of the University of Heidelberg. These so-called FG repeats, rich in the amino acids phenylalanine (F) and glycine (G), consist of hydrophobic segments linked by hydrophilic segments. To probe how these structures might be behind NPCs' molecular gatekeeping, the researchers cloned and manufactured a key, FG-repeat-rich nuclear pore protein. At high pH, solutions of this yeast nucleoporin protein remain liquid. But at physiological pH, the
protein forms hydrogels with a consistency that Frey likens to that of gummy bear candies. "Remarkably, the gels remained stable and unaltered in appearance when the temperature was raised to 95 °C," the researchers note. To investigate biochemical and physiological properties of the FG-repeats, the scientists generated mutated versions of the yeast nucleoporin and studied the effects that the changes had on the protein's function and on the viability of yeast cells expressing the mutated versions. They found strong evidence that a hydrogel-forming pattern of these motifs is essential for the survival of yeast cells. The protein's hydrogel properties lend credence to a "selective phase" model for NPC function, the INSIDE STORY researchers suggest. In this model, A nucleoporin protein that forms NTRs carry their big-molecule a hydrogel (bottom) may regulate cargo through pores because their molecular traffic through the specific interactions with FG-repores of cellular nuclei. A mutated peat regions enable these cargonucleoporin fails to gel (top). loaded units to essentially dissolve into the gelled interior of the pores. Then, with a rapid series of hand-off interactions, the NTR-cargo units steam through the pore, the gel healing itself continually behind the passing complex. "Understanding the polymer physics of the nuclear pore may inspire biomimetic materials or technological devices to capture specific macromolecules from a mixed solution," suggests materials scientist Michael Elbaum of Weizmann Institute of Science, in Rehovot, Israel, in a commentary accompanying the Science article.-IVAN AMATO
PHARMACEUTICALS Merck is to acquire Sirna, signaling confidence in RNAi therapeutics Looking to stay on the cutting edge of drug discovery, Merck & Co. has agreed to shell out $1.1 billion for Sirna Therapeutics, a San Francisco-based biotech firm focused on drugs based on RNA interference. Merck says Sirna's RNAi technology complements internal efforts on RNA expression that have been under way since its 2001 acquisition of Rosetta Inpharmatics. The company believes the technology combination could significantly change the way drugs are discovered and developed. RNAi has stirred a flood of interest,
most recently via this year's Nobel Prize in Medicine (C&EN, Oct. 9, page 8), but the technology has yet to be proven by the launch of a drug. Needham & Co. stock analyst Mark Monane says the Sirna purchase "signals a major shift in perception by large pharma about the prospects for RNAi therapeutics as a novel therapeutic class, joining the ranks of small molecules and antibodies as key drug modalities." Monane adds that the deal validates other RNAi companies, including Nastech Pharmaceutical and Alnylam, as well as those pursuing oligonucleotide drugs,
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such as Isis Pharmaceuticals. Although big pharma has flirted with RNAi—Novartis, GlaxoSmithKline, and Merck all have entered RNAi drug discovery pacts—the Sirna acquisition is the industry's first long-term commitment to the technology. For Merck, the purchase is the latest in a buying spree intended to revitalize its drug pipeline. The deal provides access to a short-interfering RNA drug that Sirna and Allergan are codeveloping to treat age-related wet macular degeneration. Earlier this year, the company paid almost $500 million combined for the biotech firms GlycoFi and Abmaxis.—LISA JARVIS
