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The Life of Proteins: the Good, the Mostly Good and the Ugly

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The Life of Proteins: the Good, the Mostly Good and the Ugly MEETING REPORT The life of proteins: the good, the mostly good and the ugly Richard I Morimoto, Arnold J M Driessen, Ramanujan S Hegde & Thomas Langer The health of the proteome in the face of multiple and diverse challenges directly influences the health of the cell and the lifespan of the organism. A recent meeting held in Nara, Japan, provided an exciting platform for scientific exchange and provocative discussions on the biology of proteins and protein homeostasis across multiple scales of analysis and model systems. The International Conference on Protein Community brought together nearly 300 scientists in Japan to exchange ideas on how proteins in healthy humans are expressed, folded, translocated, assembled and disassembled, and on how such events can go awry, leading to a myriad of protein conformational diseases. The meeting, held in Nara, Japan, in September 2010, coincided with the 1,300th birthday of Nara, Japan’s ancient capital, and provided a meditative setting for reflecting on the impact of advances in Nature America, Inc. All rights reserved. All rights Inc. America, Nature protein community research on biology and 1 1 medicine. It also provided an opportunity to consider the success of the protein community © 20 program in Japan since meetings on the stress response (Kyoto, 1989) and on the life of proteins (Awaji Island, 2005). The highlights and poster presentations. During these socials, and accessory factors. Considerable effort has of the Nara meeting were, without question, graduate and postdoctoral students and all of been and continues to be devoted toward the social periods held after long days of talks the speakers sat together on tatami mats at low understanding the mechanistic basis of protein tables replete with refreshments and enjoyed maturation and chaperone function. each other’s company, while participating in Several new concepts and methods are Richard I. Morimoto is in the Department relaxed, spirited and open discussions. bringing nascent-chain biology to the of Molecular Biosciences, Northwestern forefront of the field. Koreaki Ito (Kyoto University, Evanston, Illinois, USA and at Nascency and nascent-chain biology Sangyo University, Japan), who has studied the Rice Institute for Biomedical Research, Replenishment and renewal of the ‘protein programmed ribosomal stalling by the Evanston, Illinois, USA. Arnold J. M. Driessen community’ of cellular proteins requires Escherichia coli protein SecM, proposed that is in the Department of Molecular Microbiology, new proteins to be synthesized. A theme ribosomes have heterogeneous translation Groningen Biomolecular Sciences and that coursed throughout multiple conference speeds. He presented a two-dimensional gel Biotechnology Institute, Zernike Institute for sessions was ‘nascency’, the period between system to examine peptidyl-tRNA species, Advanced Materials, University of Groningen, initiation of the nascent chain and completion revealing the nonuniform nature of translation. Groningen, The Netherlands. Ramanujan of its assembly into a functioning product. A Ito suggested that during elongation, the S. Hegde is at the National Institute of Child nascent protein is in a particularly delicate nascent chain is ‘reviewed’ both inside and Health and Human Development, US National state, prone to inappropriate interactions, outside the ribosome to adjust translation rates, Institutes of Health, Bethesda, Maryland, USA. misfolding and aggregation. To avoid these by as-yet-unknown feedback mechanisms. Thomas Langer is at the Institute for Genetics, detrimental fates, nascent chains are guided In a global strategy to examine translation, University of Cologne, Cologne, Germany. through their maturation by molecular Jonathan Weissman (University of California, e-mail: [email protected] chaperones, modifying enzymes and targeting San Francisco) has developed ribosome NATURE STRUCTURAL & MOLECULAR BIOLOGY VOLUME 18 NUMBER 1 JANUARY 2011 1 MEETING REPORT profiling, a deep sequencing–based method to lational elongation, the nascent polypeptide, the the biogenesis and function of pre-protein accurately map the position of ribosomes on ribosome and ribosome-associating factors. translocases. Toshiya Endo (Nagoya University, all translated mRNAs. Applying this method Upon release from the ribosome, nascent Japan) discussed structural and dynamic aspects to bacterial and mammalian cells, Weissman chains fold with the assistance of chaperones. of protein import into mitochondria. Using an illustrated that sites of translational pausing Presentations by Masasuke Yoshida (Kyoto in vivo cross-linking approach, he showed that were readily detectable, opening the way for Sangyo University) and Hideki Taguchi (Tokyo the cytosol receptor domain of Tom22 in the genome-wide analyses. By preselecting the Institute of Technology, Yokohama, Japan) outer-membrane TOM40 complex changes ribosomes being analyzed, via their association addressed the function and mechanism of its interaction with another receptor subunit, with trigger factor, Weissman (in collaboration the GroEL chaperonin. Yoshida used various Tom20, to decode the pre-sequence targeting with Bernd Bukau) showed it was possible to probes such as antibody accessibility and signal. Tom22 then changes its interaction with monitor precisely when individual nascent protease digestion to show that a folded the inner-membrane pre-sequence receptor chains engage this bacterial chaperone. substrate is not completely enclosed by GroEL Tim50 to transfer the pre-sequence from In a new example of how non-uniform but rather is transiently accessible to the Tom22 to Tim50. translation is used by the cell, Kenji Kohno environment. Most substrates spend time in Mechanisms of membrane fusion events (Nara Institute of Science and Technology, a ‘tethered’ state that facilitates folding in the were analyzed in vitro by Hisao Kondo (Kyushu Japan) showed that translational pausing GroEL cage by avoiding nonproductive and University, Fukuoka, Japan) and Jodi Nunnari may facilitate mRNA localization. A transient kinetically trapped states, from which they (University of California, Davis). Kondo used an pause during Xbp1 translation, initiated when can be released to fold rapidly or can escape ER reformation assay to identify new promoting a short peptide segment enters the ribosomal and risk aggregation. Taguchi addressed the and inhibitory factors for ER reassembly, and tunnel, provides sufficient time for a preceding issue of defining GroEL substrates using a Nunnari described an in vitro mammalian hydrophobic segment to ‘drag’ the entire combination of in vitro and in vivo assays. mitochondrial fusion assay to address the ribosome–mRNA complex to the endoplasmic He reinvestigated earlier work by Hartl (Cell significance of the two outer- membrane fusion reticulum (ER) membrane. Xbp1 mRNA is 122, 209–220, 2005) and refined the classes of dynamins, MFN1 and MFN2. MFN1–MFN2 spliced by the ER-resident protein Ire1-α substrates that use the GroEL system to avoid trans-complexes showed greater efficacy in when cells experience ER stress, showing aggregation. He suggested that GroEL may fusion as compared to either alone. Moreover, that translational pausing influences mRNA help buffer destabilizing mutations in proteins, MFN2-only complexes also interacted with trafficking and splicing. Analogous work from thereby allowing their faster evolution. Bax, the proapoptotic Bcl2 protein, to regulate Ramanujan Hegde (US National Institutes Despite extensive work, little is known about mitochondrial fusion, a result that provides of Health, Bethesda, Maryland) showed that how chaperones such as GroEL or GroES further insight into the unique physiological transient pausing, just before termination of function to regulate the expression of nascent roles of these mitochondrial fusion proteins. tail-anchored membrane proteins, may facilitate chains. Takashi Yura (Kyoto University, Japan) Mitochondrial fission, discussed by Katsuyoshi recruitment of factors for targeting. One such addressed chaperone-mediated feedback Mihara (Kyushu University), is associated with factor, Bat3 (also called Bag6), was suggested control in bacteria and described a new the recruitment of the cytoplasmic dynamin- by Hegde to have a dual role in targeting and feedback-resistant mutant isolated with a related GTPase Drp1 to mitochondria. Much degradation and to function as a triage factor transposon inserted upstream of the ftsY gene as in yeast, the mitochondrial outer-membrane Nature America, Inc. All rights reserved. All rights Inc. America, Nature that facilitates degradation of improperly (encoding the bacterial signal recognition protein Fis1 is thought to be a Drp1 receptor in 1 1 targeted membrane proteins. Quite satisfyingly, particle receptor FtsY). Yura proposed that mammals. However, Mihara showed that the Weissman’s ribosomal profiling method the SRP-dependent targeting of sigma factor mitochondrial fission and fusion protein Mff, © 20 observed the pauses detected biochemically 32 to the bacterial inner membrane represents but not Fis1, functions as an essential factor in by Kohno and Hegde. Given the emerging a newly discovered step that facilitates the mitochondrial recruitment of Drp1. evidence for the diverse uses and relatively inactivation and/or degradation of sigma Although studies on membrane fusion widespread nature of translational pausing, it factor 32, in order to coordinate the cellular events have revealed their importance
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