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<jats:p> In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements, called super-enhancers, that recruit much of the cell’s transcriptional apparatus and are defined by extensive acetylation of histone H3 lysine 27 (H3K27ac). In a subset of T-cell acute lymphoblastic leukemia (T-ALL) cases, we found that heterozygous somatic mutations are acquired that introduce binding motifs for the MYB transcription factor in a precise noncoding site, which creates a super-enhancer upstream of the <jats:italic>TAL1</jats:italic> oncogene. MYB binds to this new site and recruits its H3K27 acetylase–binding partner CBP, as well as core components of a major leukemogenic transcriptional complex that contains RUNX1, GATA-3, and TAL1 itself. Additionally, most endogenous super-enhancers found in T-ALL cells are occupied by MYB and CBP, which suggests a general role for MYB in super-enhancer initiation. Thus, this study identifies a genetic mechanism responsible for the generation of oncogenic super-enhancers in malignant cells. </jats:p>

<jats:p>Despite recent advances, the structures of many proteins cannot be determined by electron cryomicroscopy because the individual proteins move during irradiation. This blurs the images so that they cannot be aligned with each other to calculate a three-dimensional density. Much of this movement stems from instabilities in the carbon substrates used to support frozen samples in the microscope. Here we demonstrate a gold specimen support that nearly eliminates substrate motion during irradiation. This increases the subnanometer image contrast such that α helices of individual proteins are resolved. With this improvement, we determine the structure of apoferritin, a smooth octahedral shell of α-helical subunits that is particularly difficult to solve by electron microscopy. This advance in substrate design will enable the solution of currently intractable protein structures.</jats:p>

<jats:p>Some HIV-infected individuals develop broadly neutralizing antibodies (bNAbs), whereas most develop antibodies that neutralize only a narrow range of viruses (nNAbs). bNAbs, but not nNAbs, protect animals from experimental infection and are likely a key component of an effective vaccine. nNAbs and bNAbs target the same regions of the viral envelope glycoprotein (Env), but for reasons that remain unclear only nNAbs are elicited by Env immunization. We show that in contrast to germline-reverted (gl) bNAbs, glnNAbs recognized diverse recombinant Envs. Moreover, owing to binding affinity differences, nNAb B cell progenitors had an advantage in becoming activated and internalizing Env compared with bNAb B cell progenitors. We then identified an Env modification strategy that minimized the activation of nNAb B cells targeting epitopes that overlap those of bNAbs.</jats:p>

<jats:p>A weekly roundup of information on newly offered instrumentation, apparatus, and laboratory materials of potential interest to researchers.</jats:p>

<jats:p>On this week's show: A bird genome bonanza and a news roundup.</jats:p>

<jats:p>China's remarkable economic rise is also propelling advances across the sciences, and these intertwined trends are transforming the western section of the country. To speed up this transformation, the Chinese Academy of Sciences (CAS), universities, and the central government are all creating award schemes aimed at attracting leading scholars trained abroad to take up positions in western China. Science centers across the region are ramping up efforts to make research teams more innovative and more international. This strategy extends to the spheres of genomics, medicine, geoscience, astronomy, physics, and conservation and is creating professional openings across the western sector of China.</jats:p>

<jats:sec> <jats:title>Introduction</jats:title> <jats:p>Evolution and design of protein complexes are frequently viewed through the lens of amino acid mutations at protein interfaces, but we showed previously that residues distant from interfaces are also commonly involved in the evolution of alternative quaternary structures. We hypothesized that in these protein families, the difference in oligomeric state is due to a change in intersubunit geometry. The indirect mutations would act by changing protein conformation and dynamics, similar to the way in which allosteric small molecules introduce functional conformational change. We refer to these substitutions as “allosteric mutations.”</jats:p> </jats:sec> <jats:sec> <jats:title>Rationale</jats:title> <jats:p>In this work, we investigate the mechanism of action of allosteric mutations on oligomeric state in the PyrR family of pyrimidine operon attenuators. In this family, an entirely sequence-conserved helix that forms a tetrameric interface in the thermophilic ortholog (BcPyrR) switches to being solvent-exposed in the mesophilic ortholog (BsPyrR). This results in a homodimeric structure in which the two subunits are clearly rotated relative to their orientation in the tetramer. What is the origin of this rotation and the change in quaternary structure? To dissect the role of the 49 substitutions between BsPyrR and BcPyrR, we used ancestral sequence reconstruction in combination with structural and biophysical methods to identify a set of allosteric mutations that are responsible for this shift in conformation. We compared the conformational changes introduced by the mutations to the protein motion during allosteric regulation by guanosine monophosphate (GMP).</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>We identified 11 key mutations controlling oligomeric state, all distant from the interfaces and outside ligand-binding pockets. We confirmed the role of these allosteric mutations by engineering a shift in oligomeric state in an inferred ancestral PyrR protein (intermediate in sequence between the extant orthologs). We further used the inferred ancestral states and their mutants to show that the allosteric mutations are part of a downhill adaptation of the PyrR proteins to lower temperatures. We compared the x-ray crystal structures of ancestral and engineered PyrR proteins to the free and GMP-bound structure of the mesophilic BsPyrR, which shifts its equilibrium from dimer to tetramer upon ligand binding. Binding of the allosteric molecule introduces a change in intersubunit geometry that is equivalent to the evolutionary difference in intersubunit geometry between the dimeric and tetrameric homologs. We further find that the difference in oligomeric state is coupled to the difference in intrinsic dynamics of the dimers. Finally, we used the residue-residue contact network approach to show that the residues corresponding to the allosteric mutations undergo large contact rewiring when the intersubunit geometry and, in turn, oligomeric state change, either by GMP binding or by the introduction of allosteric mutations.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>We show that evolution employs the intrinsic dynamics of this protein to toggle a conformational switch in a manner similar to that of small molecules. Shifting the relative populations of different states by subtle modifications is a process central to protein function and, as shown here, also to protein evolution. This suggests that we can learn from evolution and design proteins with multiple conformational states.</jats:p> </jats:sec>

<jats:p>Long before I dreamed of becoming a scientist, I wondered why Earth was teeming with life, while Mars was a barren, rocky outpost and Venus was shrouded in a dense atmosphere. Somewhere, I read that comets were the reason. Strike a rocky planet with one volatile- and organic-rich comet and an Earth-like environment results. Two comets produce a Venus. No comets: Mars. Of course, this theory was far too simple to explain the differences in the evolution of the inner planets, but no one had ever explored comets up close to know how they might alter a planet's composition and history—until now. Last month, after many years of planning and a decade in transit, the European Space Agency's spacecraft Rosetta reached Comet 67P/Churyumov-Gerasimenko, surveyed landing sites, and deployed its probe, Philae, to execute the first-ever soft landing on a comet's surface (see the News story, p. 1442).</jats:p>