In This Issue

I recent years, scientists and the media frequently have discussed the health benefits and risks associated with moderate alcohol consumption. To allow an informed debate, however, one must first define “moderate drinking” and, because many definitions of drinking levels are based on the consumption of a specific number of drinks during a certain time period, what constitutes a “drink.” Dr. Mary C. Dufour describes how the lack of a universally accepted definition of a drink may account in part for contradictory study results regarding the health consequences of moderate drinking. The differences in drink definitions and in the methodologies used to assess people’s alcohol consumption in turn lead to wide variation in definitions of “moderate drinking.” In the United States, nutritional guidelines of the U.S. Departments of Agriculture and of Health and Human Services define moderate drinking as no more than one drink per day for women and no more than two drinks per day for men. (pp. 5–14)

P53 as an ssDNA Mimic PAGE 2014 HMGB1 facilitates binding of p53 to its cognate DNA through interaction between the N-terminal region of p53 (p53N) and the HMG boxes. Rowell et al. report a structure of the complex between HMGB1 A-box and p53N showing that p53N recognizes DNA-binding face of the A box, potentially acting as an ssDNA mimic.
Linking mRNA Surveillance and Decapping PAGE 2025 The mechanism of decapping enzyme recruitment and activation during nonsense-mediated mRNA decay (NMD) remains elusive. Lai et al. characterize factors involved in NMD and show that PNRC2 binds to both Dcp1a and the key NMD factor Upf1, thereby connecting the decapping enzyme with the mRNA surveillance machinery. RIG-I is a cytosolic receptor with a role in mediating innate immunity, with two N-terminal CARD domains that get exposed upon viral RNA binding. Ferrage et al. study structure and dynamics of the second CARD and examine roles of phosphorylation in regulation of RIG-I activation in response to viral infection.

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Structural studies of multidomain proteins provide a considerable challenge due to presence of flexible regions not amenable to crystallography. Bunney et al. describe approaches to this problem that generated new insights into the structural organization and integration of individual domains comprising PLCg. The recombination process initiated by a G-quadruplex-forming sequence is critical for Neisseria gonorrhoeae pili antigenic variation. Kuryavyi et al. show that this sequence forms all-parallel-stranded monomeric 5 0 -end-stacked dimeric G-quadruplexes that can be modeled into the DNA-binding site of RecA.

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Mycobacterium tuberculosis L,D-transpeptidase 2 (Ldt Mt2 ) participates in the cell wall biosynthesis, catalyzing the 3/3 cross-link of its peptidoglycan. Erdemli et al. describe the structure of a complex of Ldt Mt2 and a peptidoglycan fragment, providing critical information about how this peptidoglycan linkages form.

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The S672R mutation in the C terminus of the human HCN4 channel severely reduces the heart rate by reducing cAMP binding. Xu et al. report a crystal structure of the mutant protein and see no global changes except in structural elements in cAMP entry-exit path, which helps stabilize the bound ligand in the binding pocket.

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Interactions of a CUE domain in the ubiquitin ligase gp78 with diverse ubiquitin chains are reported by Liu et al., who examine structure and dynamics of a CUE domain interacting with di-ubiquitin chains and suggest a mechanism for the recruitment and processive elongation of ubiquitin chains on gp78 substrates.

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The yeast EGO complex, consisting of Gtr1, Gtr2, Ego1, and Ego3, plays a pivotal role in cell growth regulation upstream of TORC1. Zhang et al. report structures of a wild-type and a mutant form of yeast, Ego3. Ego3 assumes a unique homodimeric structure essential for the integrity and function of the EGO complex.

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In vertebrates, the enzyme ecto-5'-nucleotidase (e5NT) catalyzes the hydrolysis of extracellular AMP to adenosine. A structure of e5NT reported by Knapp et al. indicates an interesting example of a multidomain protein for which a structural control of a domain movement determines substrate specificity.

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The c-jun-N-terminal-kinase (JNK) family phosphorylates many substrates and interacts with many scaffold proteins. Laughlin et al. compare crystal structures of JNK3 with three different peptides derived from either scaffold proteins or substrates and reveal an allosteric signaling mechanism of autoinhibition.

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Using single-molecule force spectroscopy Thoma et al. apply mechanical stress to one of the largest b-barrel proteins, FhuA, of the E. coli outer membrane. FhuA unfolds one b-hairpin at a time, and unfolded FhuA can't fold back, suggesting that large b-barrel membrane proteins may require cofactors for proper folding.