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Science, ISSN 0036-8075, 12/2012, Volume 338, Issue 6114, pp. 1631 - 1634
Influenza virus ribonucleoprotein complexes (RNPs) are central to the viral life cycle and in adaptation to new host species. RNPs are composed of the viral... 
RNA | Active sites | Nucleoproteins | Virions | REPORTS | Viral genomes | Orthomyxoviridae | Viruses | Viral morphology | Genomes | Electron microscopy | A VIRUS | RIBONUCLEOPROTEIN COMPLEXES | CRYSTAL-STRUCTURE | HUMAN-CELLS | NUCLEOPROTEIN | MULTIDISCIPLINARY SCIENCES | ELECTRON-MICROSCOPY | VIRAL POLYMERASE | GENERATION | BINDING | Viral Core Proteins - ultrastructure | RNA Replicase - metabolism | Influenza A Virus, H1N1 Subtype - physiology | Crystallography, X-Ray | Viral Proteins - metabolism | Influenza A Virus, H1N1 Subtype - ultrastructure | Protein Subunits - metabolism | RNA Replicase - ultrastructure | Viral Core Proteins - metabolism | Ribonucleoproteins - genetics | Transcription, Genetic | RNA, Viral - metabolism | Ribonucleoproteins - chemistry | Nucleic Acid Conformation | Influenza A Virus, H1N1 Subtype - genetics | Genome, Viral | Viral Core Proteins - chemistry | Viral Proteins - chemistry | RNA-Binding Proteins - chemistry | Models, Molecular | Ribonucleoproteins - metabolism | Viral Proteins - ultrastructure | Microscopy, Electron | Cryoelectron Microscopy | RNA-Binding Proteins - ultrastructure | RNA, Viral - chemistry | Image Processing, Computer-Assisted | Virus Replication | RNA Replicase - chemistry | Protein Conformation | Influenza A Virus, H1N1 Subtype - chemistry | Protein Subunits - chemistry | Ribonucleoproteins - ultrastructure | RNA, Viral - ultrastructure | RNA-Binding Proteins - metabolism | Influenza viruses | Properties | Ribonucleoproteins | RNA polymerase | RNA-protein interactions | Influenza | Genomics | Virology | Ribonucleic acids | Microscopy | Mortality | Replication | Online | Assembly
Journal Article
Chemistry – A European Journal, ISSN 0947-6539, 07/2018, Volume 24, Issue 40, pp. 10224 - 10230
A self‐assembly nanocomposite was designed to mimic intracellular enzymatic and non‐enzymatic antioxidants‐constituted antioxidant defense machinery. In this... 
nanozymes | self-assembly | enzymes | antioxidant machinery | reactive oxygen species | OXIDATIVE STRESS | VITAMIN-E | TOLERANCE | GLUTATHIONE-PEROXIDASE | CHEMISTRY, MULTIDISCIPLINARY | NANOPARTICLES | ARTIFICIAL ENZYMES | INFLAMMATION | SYSTEMS | MICE | SUPEROXIDE-DISMUTASE | Antioxidants | Enzymes | Selenium | Biomimetics | Glutathione peroxidase | Nanocomposites | Vitamin E | Peroxidase | Machinery | Glutathione | Machinery and equipment
Journal Article
Biomedical Journal, ISSN 2319-4170, 05/2013, Volume 36, Issue 3, pp. 106 - 117
Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of... 
Hsp90 | conformational cycle | clients | posttranslational modifications | ATPase | co-chaperones | Animals | HSP90 Heat-Shock Proteins - antagonists & inhibitors | HSP90 Heat-Shock Proteins - physiology | Humans | HSP90 Heat-Shock Proteins - chemistry | Protein Conformation | Protein Processing, Post-Translational | Molecular Chaperones - physiology | Signal transduction | Antibiotics | Protein folding | Breast cancer | Kinases | Machinery | Binding sites | Hsp90 can be secreted as well and it promotes tumor invasiveness. Blocking the secreted Hsp90 led to a significant inhibition of tumor metastasis. Structure of Hsp90 Top Structurally | nucleotide binding is not the only determinant for Hsp90 conformation. The interaction with co-chaperones and client protein also influences the conformational rearrangement of Hsp90. | p23/Sba1 | eNOS | in which the ATP lid is closed but the N-domains are still open. The N-terminal dimerization leads to the formation of the second intermediate state (I2) | while Hsp90β is constitutively expressed. Hsp90 analogues also exist in other cellular compartments such as Grp94 in the endoplasmic reticulum | the M-domain contributes to the interaction sites for client proteins and some co-chaperones. The C-domain is essential for the dimerization of Hsp90. Interestingly | Hsp90 works together with a large group of cofactors | the activation of its client protein | MutL (GHKL) domain ATPases | Therefore | Binding of Aha1 induces a partially closed Hsp90 conformation and accelerates the progression of the ATPase cycle dramatically. | Different from other well-known molecular chaperone like Hsp70 and GroEL/ES | Interestingly | 113 | which acts as a core modulator in plant immunity. During the recruitment and activation of NLRs | more than 200 Hsp90 client proteins have been identified (see http://www.picard.ch/downloads/Hsp90interactors.pdf ). Besides the well-studied clients such as protein kinases and SHRs | 115 | termed co-chaperones. Co-chaperones form defined binary or ternary complexes with Hsp90 | 116 | Our understanding of the Hsp90 machinery has been greatly advanced by research of the last decades. However | 118 | Function and Regulation of the Hsp90 Machinery. Biomed J 2013;36:106-17 How to cite this URL: Li J | leading to an asymmetric intermediate complex. Hsp90 adopts the ATPase-active (closed) conformation after binding of ATP. p23/Sba1 stabilizes the closed state of Hsp90 | and protein degradation. Interestingly | the lid segment is very flexible | and the NLR protein may dissociate from Hsp90. Hsp90 complexes in RNA processing Recent studies showed that Hsp90 is also involved in the assembly of small nucleolar ribonucleoproteins (snoRNPs) and RNA polymerase. | 15 | the lid segment promotes ATP hydrolysis. Once ATP is hydrolyzed | with 1 min–1 for yeast Hsp90 and 0.1 min–1 for human Hsp90. | hyperphosphorylation also leads to a decreased Hsp90 activity. In yeast | although a TPR domain is present in Sgt1 as well | California | Germany Date of Submission 05-Sep-2012 Date of Acceptance 02-Nov-2012 Date of Web Publication 10-Jun-2013 Correspondence Address: Johannes Buchner Center for Integrated Protein Science | the M-domain in blue | which weakens the binding of Hop/Sti1 and promotes its exit from the complex. Potentially another PPIase (dashed line) associates to form the "late complex" together with Hsp90 and p23/Sba1. After the hydrolysis of ATP | posttranslational modifications of Hsp90 | and protein degradation | 125 | 5 | the protein phosphatase PP5 (yeast homologue Ppt1) | 6 | in eukaryotic Hsp90 | such as mitochondrial/chloroplast protein import (Tom70/Toc64) | 9 | In Ppt1 knockout strains | posttranslational modifications How to cite this article: Li J | Hsp90 is a homodimer and each protomer contains three flexibly linked regions | p23 is a conformation-specific co-chaperone which binds exclusively to the closed conformation of Hsp90. | 24 | viral infection | 27 | Fkbp51 | They regulate the function of Hsp90 in different ways such as inhibition and activation of the ATPase of Hsp90 as well as recruitment of specific client proteins to the cycle. Interestingly | such as double-stranded DNA protein kinase | in which the ATP lid is closed but the N-domains are still open. Then | 132 | one of the most abundant and conserved molecular chaperones | and the C-domain in orange. Click here to view Conformational dynamics of Hsp90 Top Hsp90 is a weak ATPase and the turnover rates are very low | After fast ATP binding | Hsp90 adopts a "V"- shaped form | 35 | the maturation of protein kinases also requires the Hsp70 chaperone machinery [Figure 3]B. In the early stage | Research on the assembly of Hsp90 with SHRs had shown that several distinct complexes are formed during the maturation processes. | phosphorylation affects the conformational cycle of Hsp90 | Hsp90 stabilizes and promotes the correct folding of its client proteins | recent results imply that p53 may be destabilized by Hsp90 | and ch-Hsp90 in the chloroplast. | Chaperone cycle for protein kinases Similar to SHRs | 40 | 43 | the potentiation effects do not strictly depend on the PPIase activity of Fkbp52 as PPIase-deficient mutants are also able to potentiate GR transactivation | Technical University of Munich. Lichtenbergstrasse 4 | Notably | Nucleotide binding induces directionality and a conformational cycle. | 49 | similar heterocomplexes can be found from yeast to man even in the absence of client protein. Recent studies [using FRET | PPIase | Pih1 | co-chaperone interaction | Click here to view optimized website for mobile devices Journal is indexed with MEDLINE/Index Medicus and PubMed Share on facebookShare on twitter Share on citeulike Share on googleShare on linkedin More Sharing Services Table of Contents REVIEW ARTICLE Year : 2013 | Volume : 36 | Issue : 3 | Page : 106-117 Structure | while c-Src is largely independent of Hsp90. Notably | which implies that the tight regulation of the Hsp90 phosphorylation state is necessary for the efficient processing of client proteins. Chaperone cycle for nucleotide-binding site and leucine-rich repeat domain containing (NLR) proteins NLRs are conserved immune sensors which recognize pathogens. Accumulating evidence indicates that Hsp90 and its co-chaperones Sgt1 and Rar1 are involved in the maturation of these proteins. Sgt1 interacts with the N-domain of Hsp90 through its CS domain | acetylation | It is reasonable to assume that Hsp90 recognizes certain conformations or the stability of the client protein rather than its primary sequence. Src kinase is a prominent example here. The v-Src and its cellular counterpart (c-Src) share 95% sequence identity but distinct Hsp90 dependency. The activation of v-Src strictly depends on Hsp90 | Technische Universität München | The maturation of most SHRs strictly depends on the interaction with Hsp90. Co-chaperones such as Hop/Sti1 and the large peptidylprolyl isomerase (PPIase) have strong influences on the activation. | and the NLR protein may dissociate from Hsp90. (D) Hsp90-R2TP complex. Model of the R2TP complex in yeast. Pih1 interacts with Rvb1/2 | the phosphorylation states of Hsp90 must be precisely regulated in order to maintain the proper function of Hsp90. In addition | Hsp90 reaches a more compact state | provide another level of regulation. They influence the conformational cycle | in which first one Hop/Sti1 binds to the Hsp90 dimer and stabilizes its open conformation. As a result | 59 | was also reduced consistent with the notion thatHsp90 acts as an NO sensor. This provides a feedback mechanism to inhibit further eNOS activation. Nitrosylation or mutation of the modified C-terminal cysteine residue in Hsp90 led to an ATPase-incompetent state in which the N-terminal domains are kept in the open conformation. The result indicates that nitrosylation has a profound impact on the inter-domain communication in the Hsp90 dimer. Hsp90 client protein recognition Top To date | phosphorylation also modulates the interaction with co-chaperones and thus exerts further influence on the Hsp90 machinery. For example | PDB 2CG9). The N-domain is depicted in green | Rar1 | together with Hsp90 and a PPIase. It facilitates the maturation of client proteins by stabilizing the closed conformation of Hsp90. As a result | it is indispensable for maintaining the hormone binding activity of the glucocorticoid receptor (GR) and progesterone receptor (PR). | Aha1 is the most powerful ATPase activator of Hsp90. It binds the N- and M-domains of Hsp90. | tyrosine phosphorylation on Hsp90 disrupts the interaction with Cdc37 and promotes the recruitment of Aha1. C-terminal phosphorylation of Hsp90 regulates alternate binding to co-chaperones Chip and Hop | is partially inhibited in the presence of p23/Sba1. | which facilitate the maturation of client proteins. In addition | a new model of the chaperone cycle emerges [Figure 3]A | and Hsp90 returns to the open conformation again. Figure 2: Conformational cycle of Hsp90. After fast ATP binding | c-Src kinase | and NMR-based approaches suggested that for heat-treated p53 | more than 20 co-chaperones have been identified. | we just start to understand their contributions to client protein activation. Regulation of Hsp90 by posttranslational modifications Top Posttranslational modifications are another important regulatory element of the Hsp90 machinery. Different posttranslational modifications such as phosphorylation | which is indispensable for the release of the client protein | 60 | Hsp90 and the R2TP complex are involved in the biogenesis and assembly of snoRNPs. Notably | activation | Hsp90 and Sgt1 form a ternary complex with the co-chaperone Rar1 | proposed that Hsp90-bound p53 is in a molten globule state. In contrast | while bacteria possess an Hsp90 protein | Buchner J. Structure | such as phosphorylation and acetylation | and methylation tightly control the function of Hsp90 and thus influence the maturation of client proteins. Phosphorylation Phosphorylation is the most frequently detected posttranslational modification of Hsp90. A number of different tyrosine or serine phosphorylation sites have been identified and investigated for their impact on Hsp90's chaperone function. For example | the so-called Gyrase | which determine cellular protein folding/degradation balances. Furthermore | as it contains crucial catalytic residues for forming the composite ATPase site. Moreover | According to reconstitution experiments | and the AAA+ ATPase Rvb1 and Rvb2) has been extensively investigated [Figure 3]D. | general flexibility | In yeast | Department of Chemistry | strongly influences the binding between Hsp90 and its client protein. In general | intracellular transport | Function and Regulation of the Hsp90 Machinery. Biomed J [serial online] 2013 [cited 2014 Dec 31];36:106-17. Available from: http://www.biomedj.org/text.asp?2013/36/3/106/113230 Heat shock protein 90 (Hsp90) | a middle domain (M-domain) | Another aspect which supports the idea that Hsp90 may be involved in the ubiquitin-proteasome pathway is the discovery of a protein called carboxyl terminus of Hsp70-interacting protein (CHIP). As an E3 ubiquitin ligase | and the C-domain of Tah1. Tah1 binds to the C-terminal MEEVD motif of Hsp90 through its TPR domain. Click here to view Hop/Sti1 serves as an adaptor protein between Hsp70 and Hsp90 and facilitates the transfer of client protein. | Hsc82 and Hsp82 | belong to this group. The TPR-containing PPIases contain a PPIase domain | It was originally identified in Saccharomyces cerevisiae as a gene essential for cell cycle progression. | leading to an asymmetric Hsp90 intermediate complex. After the binding of ATP and p23/Sba1 | v-Src is an aggregation-prone protein and much more sensitive to thermal and heat denaturation than c-Src. In the case of p53 | the function of PPIases in SHR complexes is not well understood. They may be selected by specific client proteins. For example | analytical ultracentrifugation (aUC) | the Hsp90 ATPase activity is inhibited. The other TPR-acceptor site is then preferentially occupied by a PPIase | the αC-β4 loop in kinases | which consists of three TPR motifs and recognizes the C-terminal MEEVD motif in Hsp90. Besides Hop/Sti1 | and steroid hormone receptors (SHRs). | mutant CFTRΔF508 | 85747 Garching Germany Login to access the Email id Crossref citations 19 PMC citations 11 DOI: 10.4103/2319-4170.113230 PMID: 23806880 Get Permissions Abstract Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of a wide variety of client proteins and many of them are involved in important cellular pathways. Since Hsp90 affects numerous physiological processes such as signal transduction | and Cyp40 (yeast homologues Cpr6/Cpr7) | Hagn et al. reported a native-like structure of p53 interaction with Hsp90. Further analysis seems to be required to resolve this conundrum and to determine the molecular mechanism for client recognition. Hsp90 and protein degradation Top Although in general | PDB 2IOQ) and nucleotide-bound yeast Hsp90 in the closed conformation (right | In the apo state | Hsp90 reaches a fully closed state in which ATP hydrolysis occurs. After ATP is hydrolyzed | and inter-domain communication. | an N-terminal ATP-binding domain (N-domain) | bacterial Hsp90 is not essential and its precise function remains to be investigated. Recent studies suggest that it collaborates with the DnaK (Hsp70) system in substrate remodeling and may function against oxidative stress. | nitrosylation | have been discovered in recent years. | neither Hsp90 nor R2TP are components of the mature snoRNP complex. The R2TP-Hsp90 complex works together with a prefoldin-like complex in RNA polymerase II assembly. This complex interacts with unassembled Rpb1 and promotes its cytoplasmic assembly and translocation to the nucleus. In addition to the activation of client protein | 85 | CK2 protein kinase | 89 | the opening of the C-domains is anti-correlated to the closing of the N-domain. A conserved MEEVD motif at the C-terminal end serves as the docking site for the interaction with co-chaperones which contain a tetratricopeptide repeat (TPR) clamp. Figure 1: Open and closed conformation of Hsp90. Crystal structures of full-length Hsp90 from E. coli (HtpG) in the open conformation (left | release ADP as well as inorganic phosphate (Pi) | a third complex that contains a PPIase and the co-chaperone p23 had been found as the last step of the cycle. | This small acidic protein contains an unstructured C-terminal tail | Hsp90 binds the largely unfolded protein. Park et al | Histindine Kinase | which seem to be in a dynamic equilibrium [Figure 1]. | Structural studies revealed that Hsp90 spontaneously adopts structurally distinct conformations | Sgt1 has no inherent Hsp90 ATPase regulatory activity due to differences in interaction. Interestingly | many others related to | nuclear migration (NudC) | Munich | like Fkbp52 | Hsp90 adopts the "closed" conformation which weakens the binding of Hop/Sti1 and therefore promotes its exit. Another PPIase or TPR co-chaperone can potentially bind to form the final complex together with Hsp90 and p23/Sba1. Following ATP hydrolysis | biochemical experiments suggest that p53 interacts with Hsp90 in a rather folded state. | the activity of Hsp90-specific clients is significantly reduced | Hsp70 and Hsp40 interact with newly synthesized kinases. Protein kinases are recruited to Hsp90 though the action of Hop/Sti1 and the kinase-specific co-chaperone Cdc37. Both are able to stabilize the Hsp90/kinase complex. Protein phosphatase Pp5 and the ATPase activator Aha1 release Hop/Sti1 from Hsp90. At a later stage | with the M-domain of Hsp90 | co-chaperones are also involved in other physiological processes | Hsp90 is a flexible dimeric protein composed of three different domains which adopt structurally distinct conformations. ATP binding triggers directionality in these conformational changes and leads to a more compact state. To achieve its function | the interaction of Cdc37 with Hsp90 leads to the stabilization of the open conformation and the inhibition of Hsp90 ATPase activity. In contrast to the co-chaperones discussed above | it is not involved in the interaction with Hsp90. Functionally | the protein phosphatase Ppt1 deletion compromised the activation of specific clients. Therefore | and a client protein form an "early complex." The client protein is transferred from Hsp70 to Hsp90 through the adaptor protein Hop/Sti1. One Hop/Sti1 bound is sufficient to stabilize the open conformation of Hsp90. The other TPR-acceptor site is preferentially occupied by a PPIase | Recent biophysical studies using ensemble and single molecule fluorescence resonance energy transfer (FRET) assays allowed to further dissect the ATP-induced conformational changes [Figure 2]. | CHIP can ubiquitinate unfolded proteins. It also interacts with the C-terminus of Hsp70 and Hsp90 through its TPR domain. | the R2TP complex (consisting of Tah1 | and a C-terminal dimerization domain (C-domain) [Figure 1]. Except for the charged linker located between the N- and M-domains in eukaryotic Hsp90 | such as formation of the active sites | several reports have shown that Hsp90 is also required for the degradation of ER membrane proteins such as cytochrome p450 2E1 | Deacetylation of Hsp90 drives the formation of Hsp90 client complexes and promotes the maturation of the client protein GR. Hsp90 can be acetylated at different sites. A study from Necker's lab pointed out that K294 | evolutionarily conserved split ATPases | Sgt1 interacts with Hsp90 as well as with an NLR protein. In the stable ternary complex | and inter-domain communications. In this review | we discuss the recent progress made in understanding the Hsp90 machinery. Keywords: ATPase | an acetylation site in the M-domain | which suggests a noncatalytic role of PPIases in the regulation of SHR signaling. In contrast to Hop/Sti1 and the TPR-PPIases | Sgt1 is promoted to interact with Hsp90 as well as with an NLR protein. In the stable ternary complex | The co-chaperone Tah1 interacts with Hsp90 through its TPR domain and its C-terminal region binds Pih1 | and electron microscopy] provided insight into how the exchange of co-chaperones is regulated. | A number of different kinases can phosphorylate Hsp90 | the N-terminal dimerization leads to the formation of the second intermediate state (I2) | it was also found to facilitate protein degradation. In addition to soluble cytosolic proteins | which leads to the final activation of protein kinases. Cdc37 is specific for chaperoning kinases. | and thus | The presence of Aha1 enables Hsp90 to bypass the I1 state and to directly reach I2 in the ATPase cycle. The activation of specific clients such as viral Src kinase (v-Src) and SHRs is severely affected in Aha1 knockout cells. Moreover | of which Hsp82 is up-regulated up to 20 times under heat stress. Hsp90α and Hsp90β are the two major isoforms in the cytoplasm of mammalian cells. Hsp90α is inducible under stress conditions | Hsp70 and Hsp40 interact with newly synthesized kinases. Protein kinases are recruited to Hsp90 through the action of Hop/Sti1 and the kinase-specific co-chaperone Cdc37. Both are able to stabilize the Hsp90/kinase complex. At a later stage | Aha1 can release Cdc37 from Hsp90 together with nucleotides. (C) Hsp90 chaperone cycle for NLRs. Rar1 binds to the N-domain of Hsp90 through its Chord1 domain and prevents the formation of the closed conformation. This interaction supports the binding of Rar1-Chord2 to the N-domain in the other protomer. With the association of Rar1-Chord2 | this domain organization is conserved from bacteria to man. Hsp90 is a member of a special class of structurally related | which is structurally similar to p23/Sba1. | called HtpG in Escherichia More Details coli | and members of the PPIase family | Mammalian Hsp90 is a target of S-nitrosylation mediated by NO produced by its client protein | Cyp40 is most abundant in estrogen receptor (ER) complexes and Fkbp52 mediates potentiation of GR through increasing GR hormone-binding affinity. Interestingly | there are two Hsp90 isoforms in the cytosol | no Hsp90 gene has been found in archea. | Johannes Buchner2 1 Division of Biology | the central player in this process | different co-chaperones work together to facilitate the maturation of Hsp90 clients. The composition of co-chaperone complexes seems to depend to some degree on the presence of a specific client protein. The chaperone cycle for SHRs Early work on Hsp90 mainly focused on the co-chaperone requirement for the activation of SHRs. | These results suggest that there may be a dynamic equilibrium between the different conformations of Hsp90 and this conformational plasticity is functionally important since it may allow Hsp90 to adapt to different client proteins. Co-chaperone regulation of Hsp90 Top Co-chaperone regulation is a conserved feature of the eukaryotic Hsp90 system. To date | which catalyzes the interconversion of the cis-trans isomerization of peptide bonds prior to proline residues and a TPR domain for the interaction with Hsp90. Most of these large PPIases show independent chaperone activity. | nuclear magnetic resonance (NMR) spectroscopy | Hsp90 does not only function in protein folding but also contribute to various cellular processes including signal transduction | which contain a Bergerat ATP-binding fold. Another interesting feature of the ATP binding region is that several conserved amino acid residues form a "lid" that closes over the nucleotide binding pocket in the ATP-bound state but is open during the ADP-bound state. The M-domain of Hsp90 is involved in ATP hydrolysis |