Structure of an Hsp90-Cdc37-Cdk4 complex

Activation of many protein kinases depends on their interaction with the Hsp90 molecular chaperone system. Recruitment of protein kinase clients to the Hsp90 chaperone system is mediated by the cochaperone adaptor protein Cdc37, which acts as a scaffold, simultaneously binding protein kinases and Hsp90. We have now expressed and purified an Hsp90-Cdc37-Cdk4 complex, defined its stoichiometry, and determined its 3D structure by single-particle electron microscopy. Comparison with the crystal structure of Hsp90 allows us to identify the locations of Cdc37 and Cdk4 in the complex and suggests a mechanism by which conformational changes in the kinase are coupled to the Hsp90 ATPase cycle

Comparative analysis of the transcriptome across distant species

The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features. Specifically, we discover co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we use expression patterns to align the stages in worm and fly development and find a novel pairing between worm embryo and fly pupae, in addition to the embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we find that the extent of non-canonical, non-coding transcription is similar in each organism, per base pair. Finally, we find in all three organisms that the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a 'universal model' based on a single set of organism-independent parameters

The structure of the cell cycle protein Cdc14 reveals a proline-directed protein phosphatase

The Cdc14 family of dual-specificity protein phosphatases (DSPs) is conserved within eukaryotes and functions to down-regulate mitotic Cdk activities, promoting cytokinesis and mitotic exit. We have integrated structural and kinetic analyses to define the molecular mechanism of the dephosphorylation reaction catalysed by Cdc14. The structure of Cdc14 illustrates a novel arrangement of two domains, each with a DSP-like fold, arranged in tandem. The C-terminal domain contains the conserved PTP motif of the catalytic site, whereas the N-terminal domain, which shares no sequence similarity with other DSPs, contributes to substrate specificity, and lacks catalytic activity. The catalytic site is located at the base of a pronounced surface channel formed by the interface of the two domains, and regions of both domains interact with the phosphopeptide substrate. Specificity for a pSer-Pro motif is mediated by a hydrophobic pocket that is capable of accommodating the apolar Pro(P+1) residue of the peptide. Our structural and kinetic data support a role for Cdc14 in the preferential dephosphorylation of proteins modified by proline-directed kinases

Structural basis for recruitment of glycogen synthase kinase 3β to the axin–APC scaffold complex

Glycogen synthase kinase 3β (GSK3β) is a serine/threonine kinase involved in insulin, growth factor and Wnt signalling. In Wnt signalling, GSK3β is recruited to a multiprotein complex via interaction with axin, where it hyperphosphorylates β-catenin, marking it for ubiquitylation and destruction. We have now determined the crystal structure of GSK3β in complex with a minimal GSK3β-binding segment of axin, at 2.4 Å resolution. The structure confirms the co-localization of the binding sites for axin and FRAT in the C-terminal domain of GSK3β, but reveals significant differences in the interactions made by axin and FRAT, mediated by conformational plasticity of the 285–299 loop in GSK3β. Detailed comparison of the axin and FRAT GSK3β complexes allows the generation of highly specific mutations, which abrogate binding of one or the other. Quantitative analysis suggests that the interaction of GSK3β with the axin scaffold enhances phosphorylation of β-catenin by >20 000-fold

Learning from leading women's experience:towards a sociological understanding

Conceptions of leadership draw largely on the leadership experiences of a limited population, and of those in a restricted range of organizational settings. This article begins to address some of these biases by examining the experiences of six leading women in differing sectors. In researching the `how' of leadership there emerges a web of four inter-related factors that connects these leaders to their community and that plays a foundational role in their lives: upbringing, environment, focus and networks and alliances. The ways in which leadership is experienced and constructed by women, the article therefore argues, can be made more sense of through a sociological lens, and raises questions about how tendencies in research sites lead to gendered and individualistic understandings of leadership. In illuminating the need to make the distinction between representations of leadership and our experience of leadership, the article concludes that leadership is not just about leading people, but is often pioneering and can include the leadership of ideas, communities, and the representation of issue