An unanticipated architecture of the 750-kDa α6β6 holoenzyme of 3-methylcrotonyl-CoA carboxylase

3-Methylcrotonyl-CoA carboxylase (MCC), a member of the biotin-dependent carboxylase superfamily, is essential for the metabolism of leucine, and deficient mutations in this enzyme are linked to methylcrotonylglycinuria (MCG) and other serious diseases in humans. MCC has strong sequence conservation with propionyl-CoA carboxylase (PCC), and their holoenzymes are both 750-kilodalton (kDa) α(6)β(6) dodecamers. Therefore the architecture of the MCC holoenzyme is expected to be highly similar to that of PCC. Here we report the crystal structures of the Pseudomonas aeruginosa MCC (PaMCC) holoenzyme, alone and in complex with coenzyme A. Surprisingly, the structures show that the architecture and overall shape of PaMCC are markedly different when compared to PCC. The α-subunits show trimeric association in the PaMCC holoenzyme, whereas they have no contacts with each other in PCC. Moreover, the positions of the two domains in the β-subunit of PaMCC are swapped relative to those in PCC. This structural information establishes a foundation for understanding the disease-causing mutations of MCC and provides new insights into the catalytic mechanism and evolution of biotin-dependent carboxylases. The large structural differences between MCC and PCC also have general implications for the relationship between sequence conservation and structural similarity.     

Charles Darwin and the repugnant curators

Recently discovered documents have revealed the background to a letter published in The Darwin Correspondence, dated 21 February 1838 and sent to Charles Darwin and six others from John George Children of the British Museum. It concerned a complaint made by Edward Blyth about George Robert Gray, assistant in charge of birds at the museum. A response by Darwin, and 14 other referees, supported Gray's defence of his character, and the complaint was dismissed. It is concluded that Children investigated this complaint so vigorously because of recent criticism of the natural history collections by witnesses to the Select Committee of the House of Commons on the British Museum (1836–37), who sought to increase the involvement and influence of career scientists in the overseeing of the collections. Children may have also been sensitive to criticism because he was a controversial appointee.     

Isotopic portrayal of the Earth's upper mantle flow field

It is now well established that oceanic plates sink into the lower mantle at subduction zones, but the reverse process of replacing lost upper-mantle material is not well constrained. Even whether the return flow is strongly localized as narrow upwellings or more broadly distributed remains uncertain. Here we show that the distribution of long-lived radiogenic isotopes along the world's mid-ocean ridges can be used to map geochemical domains, which reflect contrasting refilling modes of the upper mantle. New hafnium isotopic data along the Southwest Indian Ridge delineate a sharp transition between an Indian province with a strong lower-mantle isotopic flavour and a South Atlantic province contaminated by advection of upper-mantle material beneath the lithospheric roots of the Archaean African craton. The upper mantle of both domains appears to be refilled through the seismically defined anomaly underlying South Africa and the Afar plume. Because of the viscous drag exerted by the continental keels, refilling of the upper mantle in the Atlantic and Indian domains appears to be slow and confined to localized upwellings. By contrast, in the unencumbered Pacific domain, upwellings seem comparatively much wider and more rapid.     

C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a

Complement-derived anaphylatoxins regulate immune and inflammatory responses through G-protein-coupled receptor (GPCR)-mediated signalling. C5L2 (also known as GPR77) is a relatively new GPCR thought to be a non-signalling receptor binding to C5a, on the basis of sequence information and experimental evidence. Here we show, using gene targeting, that C5L2 is required to facilitate C5a signalling in neutrophils, macrophages and fibroblasts in vitro. Deficiency of C5L2 results in reduced inflammatory cell infiltration, suggesting that C5L2 is critical for optimal C5a-mediated cell infiltration in certain in vivo settings. C5L2 is also involved in optimizing C3a-induced signals. Furthermore, like mice incapable of C3a/complement 3a receptor (C3aR) signalling, C5L2-deficient mice are hypersensitive to lipopolysaccharide (LPS)-induced septic shock, show reduced ovalbumin (OVA)-induced airway hyper-responsiveness and inflammation, and are mildly delayed in haematopoietic cell regeneration after gamma-irradiation. Our data indicate that C5L2 can function as a positive modulator for both C5a- and C3a-anaphylatoxin-induced responses.     

Dosage compensation of the active X chromosome in mammals

Monosomy of the X chromosome owing to divergence between the sex chromosomes leads to dosage compensation mechanisms to restore balanced expression between the X and the autosomes. In Drosophila melanogaster, upregulation of the male X leads to dosage compensation. It has been hypothesized that mammals likewise upregulate their active X chromosome. Together with X inactivation, this mechanism would maintain balanced expression between the X chromosome and autosomes and between the sexes. Here, we show that doubling of the global expression level of the X chromosome leads to dosage compensation in somatic tissues from several mammalian species. X-linked genes are highly expressed in brain tissues, consistent with a role in cognitive functions. Furthermore, the X chromosome is expressed but not upregulated in spermatids and secondary oocytes, preserving balanced expression of the genome in these haploid cells. Upon fertilization, upregulation of the active X must occur to achieve the observed dosage compensation in early embryos.