Molecular guardians for newborn proteins: ribosome-associated chaperones and their role in protein folding

Wegrzyn, Renee D.; Deuerling, Elke

doi:10.1007/s00018-005-5292-z

Cited by 79 publications

(52 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is likely that Hsp70 and Hsp90 promote the synthesis of p27, as seen for the synthesis of flock house virus protein A (4, 91). Alternatively, it is possible that the translating p27 is protected from degradation by a ribosome-associated chaperone system, in which Hsp70 is thought to interact directly with nascent polypeptides emerging from ribosomes (37,92). Cotranslational binding of Hsp70 and/or Hsp90 might facilitate the subsequent function of these chaperones during the assembly of the RCNMV replicase complex.…”

Section: Discussionmentioning

confidence: 99%

Differential Roles of Hsp70 and Hsp90 in the Assembly of the Replicase Complex of a Positive-Strand RNA Plant Virus

Mine

Hyodo

Tajima

et al. 2012

J Virol

View full text Add to dashboard Cite

Japan bAssembly of viral replicase complexes of eukaryotic positive-strand RNA viruses is a regulated process: multiple viral and host components must be assembled on intracellular membranes and ordered into quaternary complexes capable of synthesizing viral RNAs. However, the molecular mechanisms underlying this process are poorly understood. In this study, we used a model virus, Red clover necrotic mosaic virus (RCNMV), whose replicase complex can be detected readily as the 480-kDa functional protein complex. We found that host heat shock proteins Hsp70 and Hsp90 are required for RCNMV RNA replication and that they interact with p27, a virus-encoded component of the 480-kDa replicase complex, on the endoplasmic reticulum membrane. Using a cell-free viral translation/replication system in combination with specific inhibitors of Hsp70 and Hsp90, we found that inhibition of p27-Hsp70 interaction inhibits the formation of the 480-kDa complex but instead induces the accumulation of large complexes that are nonfunctional in viral RNA synthesis. In contrast, inhibition of p27-Hsp90 interaction did not induce such large complexes but rendered p27 incapable of binding to a specific viral RNA element, which is a critical step for the assembly of the 480-kDa replicase complex and viral RNA replication. Together, our results suggest that Hsp70 and Hsp90 regulate different steps in the assembly of the RCNMV replicase complex. Most plant and animal viruses are positive-strand RNA viruses, which have single-stranded messenger-sense genomic RNAs. These viruses often induce host membrane rearrangements to form organelle-like compartments in which viral genomic RNAs are replicated via negative-strand RNA intermediates by the viral replicase complexes (10). Viral replicase complexes comprise multiple proteins, including viral auxiliary proteins, viral RNAdependent RNA polymerase (RdRP), and host proteins (61). Viral replicase complexes have been studied extensively by characterizing their RdRP activities and the functions of the viral and host components of the complexes. These studies have provided important information about the mechanisms regulating genome replication (15, 19, 47, 89), viral pathogenicity (68, 69), and virushost interactions (24,25,32,33). However, an important question remains: how do multiple viral and host components assemble properly into the replicase complex?Molecular chaperones are essential for cell viability by ensuring folding of newly synthesized proteins, refolding of misfolded or aggregated proteins, protein complex assembly and disassembly, membrane translocation of organellar and secretory proteins, protein degradation, and activities of regulatory proteins in signal transduction pathways (12,18,51). In eukaryotic cells, the abundant and highly conserved molecular chaperones heat shock proteins Hsp70 and Hsp90 play central roles in the biological processes mentioned above, and the activities of Hsp70 and Hsp90 are modulated by a variety of cochaperones (37,80). Considering their pivotal roles i...

show abstract

Section: Discussionmentioning

confidence: 99%

Differential Roles of Hsp70 and Hsp90 in the Assembly of the Replicase Complex of a Positive-Strand RNA Plant Virus

Mine

Hyodo

Tajima

et al. 2012

J Virol

View full text Add to dashboard Cite

show abstract

“…Among these are components of the RAC complex, which includes ribosome-binding Hsp70 and Hsp40 chaperones that promote efficient polypeptide translation (50). Other members of the Hsp70 and Hsp110 families also participate in nascent chain binding (55).…”

Section: Discussionmentioning

confidence: 99%

Ydj1 Protects Nascent Protein Kinases from Degradation and Controls the Rate of Their Maturation

Mandal

Nillegoda

Chen

et al. 2008

Molecular and Cellular Biology

View full text Add to dashboard Cite

Ydj1 is a Saccharomyces cerevisiae Hsp40 molecular chaperone that functions with Hsp70 to promote polypeptide folding. We identified Ydj1 as being important for maintaining steady-state levels of protein kinases after screening several chaperones and cochaperones in gene deletion mutant strains. Pulse-chase analyses revealed that a portion of Tpk2 kinase was degraded shortly after synthesis in a ydj1⌬ mutant, while the remainder was capable of maturing but with reduced kinetics compared to the wild type. Cdc28 maturation was also delayed in the ydj1⌬ mutant strain. Ydj1 protects nascent kinases in different contexts, such as when Hsp90 is inhibited with geldanamycin or when CDC37 is mutated. The protective function of Ydj1 is due partly to its intrinsic chaperone function, but this is minor compared to the protective effect resulting from its interaction with Hsp70. SIS1, a type II Hsp40, was unable to suppress defects in kinase accumulation in the ydj1⌬ mutant, suggesting some specificity in Ydj1 chaperone action. However, analysis of chimeric proteins that contained the chaperone modules of Ydj1 or Sis1 indicated that Ydj1 promotes kinase accumulation independently of its client-binding specificity. Our results suggest that Ydj1 can both protect nascent chains against degradation and control the rate of kinase maturation.

show abstract

“…The NAC is a heterodimeric complex that associates with ribosomes near the polypeptide exit tunnel. 31 Although the function of the NAC is poorly defined, it is thought to have roles in co-translational protein folding 32 and in protein targeting to mitochondria 33 and the endoplasmic reticulum. 34 The RAC consists of the Heat Shock Protein (Hsp) 70/40 pair Ssz1/ Zuo1, 35 which is anchored to the ribosome in close proximity to the polypeptide exit tunnel via a charged C-terminal region of Zuo1.…”

Section: Introductionmentioning

confidence: 99%

The ribosome-associated complex antagonizes prion formation in yeast

Amor

Castanzo

Delany

et al. 2015

Prion

View full text Add to dashboard Cite

ABSTRACT. The number of known fungal proteins capable of switching between alternative stable conformations is steadily increasing, suggesting that a prion-like mechanism may be broadly utilized as a means to propagate altered cellular states. To gain insight into the mechanisms by which cells regulate prion formation and toxicity we examined the role of the yeast ribosome-associated complex (RAC) in modulating both the formation of the [PSI C ] prion -an alternative conformer of Sup35 protein -and the toxicity of aggregation-prone polypeptides. The Hsp40 RAC chaperone Zuo1 anchors the RAC to ribosomes and stimulates the ATPase activity of the Hsp70 chaperone Ssb. We found that cells lacking Zuo1 are sensitive to over-expression of some aggregation-prone proteins, including the Sup35 prion domain, suggesting that co-translational protein misfolding increases in Dzuo1 strains. Consistent with this finding, Dzuo1 cells exhibit higher frequencies of spontaneous and induced prion formation. Cells expressing mutant forms of Zuo1 lacking either a C-terminal charged region required for ribosome association, or the J-domain responsible for Ssb ATPase stimulation, exhibit similarly high frequencies of prion formation. Our findings are consistent with a role for the RAC in chaperoning nascent Sup35 to regulate folding of the N-terminal prion domain as it emerges from the ribosome.

show abstract

Molecular guardians for newborn proteins: ribosome-associated chaperones and their role in protein folding

Cited by 79 publications

References 96 publications

Differential Roles of Hsp70 and Hsp90 in the Assembly of the Replicase Complex of a Positive-Strand RNA Plant Virus

Differential Roles of Hsp70 and Hsp90 in the Assembly of the Replicase Complex of a Positive-Strand RNA Plant Virus

Ydj1 Protects Nascent Protein Kinases from Degradation and Controls the Rate of Their Maturation

The ribosome-associated complex antagonizes prion formation in yeast

Contact Info

Product

Resources

About