Advances on the structure of the R2TP/Prefoldin-like complex

Cellular stability, assembly and activation of a growing list of macromolecular complexes require the action of HSP90 working in concert with the R2TP/Prefoldin-like (R2TP/PFDL) co-chaperone. RNA polymerase II, snoRNPs and complexes of PI3-kinase-like kinases, a family that includes the ATM, ATR, DNA-PKcs, TRAPP, SMG1 and mTOR proteins, are among the clients of the HSP90-R2TP system. Evidence links the R2TP/PFDL pathway with cancer, most likely because of the essential role in pathways commonly deregulated in cancer. R2TP forms the core of the co-cochaperone and orchestrates the recruitment of HSP90 and clients, whereas prefoldin and additional prefoldin-like proteins, including URI, associate with R2TP, but their function is still unclear. The mechanism by which R2TP/PFLD facilitates assembly and activation of such a variety of macromolecular complexes is poorly understood. Recent efforts in the structural characterization of R2TP have started to provide some mechanistic insights. We summarize recent structural findings, particularly how cryo-electron microscopy (cryo-EM) is contributing to our understanding of the architecture of the R2TP core complex. Structural differences discovered between yeast and human R2TP reveal unanticipated complexities of the metazoan R2TP complex, and opens new and interesting questions about how R2TP/PFLD works

The ‘Complex World’ of the Hsp90 Co-chaperone R2TP

The Hsp90 co-chaperone R2TP consists of the AAA+ ATPases, RUVBL1 (Rvb1p in yeast) and RUVBL2 (Rvb2 in yeast), which together make up a heterohexameric ring, in complex with PIH1D1 (Pih1p in yeast) and RPAP3 (Tah1p in yeast). R2TP is involved in the activation of client proteins, such as phosphatidylinositol 3 kinase-related kinases, including mTORC1, ATM, DNA-PK, SMG and ATR/ATRIP, or in the assembly of protein complexes including those of RNA polymerase and snoRNPs, amongst others. In other cases, the role of the TP component (RPAP3-PIH1D1) of R2TP, and consequently Hsp90, is controversial. None-the-less, the extensive role of RUVBL1-RUVBL2 complex in cells, either with or without Hsp90, means that dysfunction of these AAA+ ATPases, Hsp90 or components of the complexes they assemble leads to diseases such as cancer, ciliary dyskinesia and in the case of defects in ATM to ataxia telangiectasia-like syndrome. Recent advances in determining the structure of the R2TP complex has led to an increased understanding of the assembly and function of the R2TP complex. In this review we discuss the current structural advances in determining the architecture of the R2TP complex and the advances made in understanding its active state

How novel structures inform understanding of complement function

33 p.-3 fig.During the last decade, the complement field has experienced outstanding advancements in the mechanistic understanding of how complement activators are recognized, what C3 activation means, how protein complexes like the C3 convertases and the membrane attack complex are assembled, and how positive and negative complement regulators perform their function. All of this has been made possible mostly because of the contributions of structural biology to the study of the complement components. The wealth of novel structural data has frequently provided support to previously held knowledge, but often has added alternative and unexpected insights into complement function. Here we will review some of these findings focusing in the alternative and terminal complement pathways.SRdeC is supported by the Spanish “Ministerio de Economía y Competitividad-FEDER” (SAF2015-66287R), the Seventh Framework Programme European Union Project EURenOmics (305608) and the Autonomous Region of Madrid (S2010/BMD- 2316). SRdeC is member of the “CIB intramural Program “Molecular Machines for Better Life (MACBET)”. EGdeJ is supported by the Spanish “Ministerio de Economía y Competitividad-FEDER” (RYC-2013-13395 and SAF2014-52339P). OL is supported by the Spanish Ministry of Economy, Industry and Competitiveness (SAF2014-52301-R).AT and MS are supported by the Spanish “Ministerio de Economía y Competitividad-FEDER” (IJCI-2015-25222 and IJCI-2015-24388, respectively).Peer reviewe