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• W2087689873 abstract "In living cells, both newly made and preexisting polypeptide chains are at constant risk for misfolding and aggregation. In accordance with the wide diversity of misfolded forms, elaborate quality-control strategies have evolved to counter these inevitable mishaps. Recent reports describe the removal of aggregates from the cytosol; reveal mechanisms for protein quality control in the endoplasmic reticulum; and provide new insight into two classes of molecular chaperones, the Hsp70 system and the AAA+ (Hsp100) unfoldases. In living cells, both newly made and preexisting polypeptide chains are at constant risk for misfolding and aggregation. In accordance with the wide diversity of misfolded forms, elaborate quality-control strategies have evolved to counter these inevitable mishaps. Recent reports describe the removal of aggregates from the cytosol; reveal mechanisms for protein quality control in the endoplasmic reticulum; and provide new insight into two classes of molecular chaperones, the Hsp70 system and the AAA+ (Hsp100) unfoldases. Main TextProtein Folding in the Endoplasmic Reticulum: Knowing Right from WrongThe endoplasmic reticulum (ER) is responsible for the structural maturation of the roughly one-quarter of the proteome that traverses the secretory pathway (Anken et al., 2005Anken E. Braakmann I. Craig E. Versatility of the endoplasmic reticulum protein folding factory.Crit. Rev. Biochem. Mol. Biol. 2005; 40: 191-228Crossref PubMed Scopus (164) Google Scholar). Folding of secretory proteins provides a number of unique challenges. Folding is often accompanied by and dependent on the formation of correct native disulfide bonds and insertion into the lipid bilayer, with both events occurring more slowly by orders of magnitude than the typical conformational changes that accompany folding. Correspondingly, the ER provides an environment optimized to face these challenges, including high concentrations of general chaperones as well as a range of strategies specifically tailored to aid folding of secretory proteins. Additionally, a sophisticated quality-control system exists in the ER to retain and retrieve proteins that have not yet reached their native state (Ellgaard and Helenius, 2003Ellgaard L. Helenius A. Quality control in the endoplasmic reticulum.Nat. Rev. Mol. Cell Biol. 2003; 4: 181-191Crossref PubMed Scopus (1656) Google Scholar).Despite the lengths to which the cell goes to provide an optimized environment in the ER, folding of secretory proteins can and does fail, at times at an alarming rate. The ER employs two distinct mechanisms for responding to the presence of misfolded forms. The first is an ER-dedicated stress response termed the unfolded protein response (UPR), which acts to remodel the ER so as to increase its folding capacity (Schroder and Kaufman, 2005Schroder M. Kaufman R.J. The mammalian unfolded protein response.Annu. Rev. Biochem. 2005; 74: 739-789Crossref PubMed Scopus (2403) Google Scholar). The second, termed ER-associated degradation (ERAD), specifically recognizes terminally misfolded proteins and retrotranslocates them across the ER membrane into the cytosol, where they can be degraded by the ubiquitin-proteasome degradation machinery (Romisch, 2005Romisch K. Endoplasmic reticulum-associated degradation.Annu. Rev. Cell Dev. Biol. 2005; 21: 435-456Crossref PubMed Scopus (275) Google Scholar). These two systems are intimately linked: UPR induction increases ERAD capacity, loss of ERAD leads to constitutive UPR induction, and simultaneous loss of ERAD and the UPR greatly decreases cell viability. The UPR and ERAD systems also face the common problem of recognition, which requires the identification of potentially pathological misfolded forms in an ER environment that is constitutively filled with normal on-pathway folding intermediates. UPR and ERAD surveillance must strike a fine balance, protecting the cell from dangerous misfolded species while avoiding overvigilance (as happens with mutant forms of the cystic fibrosis transmembrane regulator [CFTR]), which can lead to the disposal of potentially remediable forms. Recent advances reveal how the UPR and ERAD identify misfolded forms.The Unfolded Protein ResponseIn yeast, the folding capacity of the ER is monitored by IRE1, a highly conserved transmembrane kinase that contains a lumenal domain responsible for sensing misfolded forms and cytosolic kinase and ribonuclease domains. The accumulation of misfolded proteins in the ER leads to activation of the IRE kinase. IRE kinase activation promotes the nonconventional splicing of the message for a b-ZIP transcription factor (Hac1p in yeast and XBP-1 in metazoans) via its ribonuclease domain. Translation of the spliced Hac1 message creates an active transcription factor that directly mediates transcription of UPR targets including ER chaperones, the ERAD machinery, and a range of other secretory proteins.In addition to IRE1, higher eukaryotes utilize two other sensors, the ER transmembrane kinase PERK and the ER transmembrane transcription factor ATF6. PERK contains a lumenal sensor that is highly related to that of IRE1, but, unlike IRE1, the PERK cytoplasmic domain consists of an eIF2α kinase. Activation of the kinase by the presence of misfolded proteins results in a generalized inhibition of translation as well as the upregulation of a specific transcription factor, ATF4. Accumulation of misfolded proteins also allows ATF6 to reach the Golgi, where transmembrane proteases release the cytoplasmic transcription-factor domain, allowing it to enter the nucleus and mediate gene induction. The existence of multiple UPR sensors in higher eukaryotes allows for a more nuanced response to misfolded proteins. For example, an initial response to protein misfolding could be a generalized downregulation of translation, followed in sequence by induction of chaperones; the induction of the ERAD machinery; and ultimately, in the face of prolonged stress, activation of cell death via apoptosis.Very recently there have been exciting advances in our molecular understanding of how IRE1 (and, by inference, PERK) recognizes misfolded proteins. Earlier studies observed that the major ER-localized Hsp70 homolog BiP specifically binds IRE1 and that this interaction disappears under conditions of ER stress. Additionally, overexpression of BiP can suppress the induction of the UPR. This had suggested a titration model, in which BiP acts as a negative regulator of IRE1 and the accumulation of misfolded forms leads indirectly to IRE1 activation by the sequestration of BiP by misfolded proteins. However, recent studies indicate that although BiP binding is likely to play an important role in down regulating IRE1, it is not the whole story. Mutational analysis found that deletion of the region of IRE1 responsible for BiP binding did not impair the regulation of IRE1 in the response to unfolded protein (Kimata et al., 2004Kimata Y. Oikawa D. Shimizu Y. Ishiwata-Kimata Y. Kohno K. A role for BiP as an adjustor for the endoplasmic reticulum stress-sensing protein Ire1.J. Cell Biol. 2004; 167: 445-456Crossref PubMed Scopus (214) Google Scholar). More dramatically, the crystal structure of the conserved core lumenal domain (cLD) of yeast IRE1 reveals a deep hydrophobic groove reminiscent of the binding pocket in the major histocompatibility complexes (MHCs) that is responsible for peptide recognition. That IRE1 may directly bind misfolded polypeptides is an appealing idea (Figure 1) (Credle et al., 2005Credle J.J. Finer-Moore J.S. Papa F.R. Stroud R.M. Walter P. On the mechanism of sensing unfolded protein in the endoplasmic reticulum.Proc. Natl. Acad. Sci. USA. 2005; 102: 18773-18784Crossref PubMed Scopus (397) Google Scholar). By directly recognizing misfolded forms, the initiation of IRE1 induction could occur prior to the full titration of BiP, which, given BiP's extremely high abundance in the ER, might occur only after a catastrophic accumulation of misfolded proteins. Additionally, direct recognition of misfolded forms by IRE1 (and PERK) could allow for a more nuanced set of responses in which different misfolded forms could be preferentially recognized by the different sensors (BiP, IRE1, or PERK). Thus, in principle, the nature (e.g., translational versus transcriptional) and timing of the UPR could be tailored to the specific class of misfolded forms that are prevalent in the ER.Endoplasmic Reticulum-Associated DegradationAs might be expected by the diversity of proteins that fold in the ER, recent studies argue that ER-associated degradation (ERAD) encompasses a number of different systems, each responsible for the degradation of subsets of proteins that share common physical properties. This is perhaps most clearly shown in yeast, where there are at least two distinct surveillance mechanisms for identifying terminally misfolded ER proteins. The first, designated ERAD-L, inspects for proteins that contain misfolded lumenal (soluble or membrane-tethered) domains such as CPY∗, a mutant form of the endogenous CPY protein that is incapable of folding. The second, termed ERAD-C, detects misfolded cytosolic domains of transmembrane proteins (Vashist and Ng, 2004Vashist S. Ng D.T. Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control.J. Cell Biol. 2004; 165: 41-52Crossref PubMed Scopus (359) Google Scholar). Although both of these pathways ultimately converge on the ubiquitin-proteasome degradation system, they depend on different sets of ER-associated components to detect and deliver misfolded species to the cytosol. In the case of ERAD-C (but not ERAD-L), degradation is typically dependent on a specific subset of cytosolic chaperones including Hsp70 and Hsp40 members (Nishikawa et al., 2005Nishikawa S. Brodsky J.L. Nakatsuka K. Role of molecular chaperones in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD).J. Biochem. (Tokyo). 2005; 137: 551-555Crossref PubMed Scopus (128) Google Scholar). This suggests that these proteins may be directly responsible for recognizing misfolded cytosolic domains of transmembrane proteins. However, the exact features that are being monitored and how substrates are delivered to the retrotranslocation machinery remain important open questions for most substrates.The recognition of a protein containing a misfolded lumenal domain is critically dependent on the protein's glycosylation status (Helenius and Aebi, 2004Helenius A. Aebi M. Roles of N-linked glycans in the endoplasmic reticulum.Annu. Rev. Biochem. 2004; 73: 1019-1049Crossref PubMed Scopus (1593) Google Scholar). Indeed, even minor alterations of N-linked glycans can lead to severe defects in the degradation of a number of substrates. This can effectively leave proteins in limbo: Unable to reach the native state but not recognized by the ERAD machinery, they remain misfolded in the ER indefinitely. At first blush, this reliance on glycosylation appears to be an unneeded embellishment. However, it is now clear that the spectrum of sugar moieties present on a protein is a key signal in marking its folding status. Indeed, given that several highly abundant proteins resident in the ER, including BiP and PDI, are often not glycosylated, the presence and covalent nature of high-mannose sugars on a polypeptide may provide an important signal that helps the ER quality-control machinery to distinguish folding species destined for other compartments from the more abundant permanent residents of the ER. Insight into the role of glycosylation in the discrimination between on-pathway folding species and terminally misfolded proteins in the ER has come from the finding that misfolded glycoproteins undergo trimming of their N-glycans by a variety of glycosidases including a specific mannosidase. In conjunction with persistent protein misfolding, the time-dependent remodeling of N-glycans is thought to result in a bipartite signal for degradation by the ERAD machinery. This affords folding intermediates a period of time, before the remodeling of their N-glycans, in which the polypeptide is immune from surveillance by the ERAD machinery. Interestingly, a recent study suggests that even for cytosolic polypeptides, there is a period during and shortly after synthesis in which misfolded species are immune from degradation by the proteasome machinery (Vabulas and Hartl, 2005Vabulas R.M. Hartl F.U. Protein synthesis upon acute nutrient restriction relies n proteasome function.Science. 2005; 310: 1960-1963Crossref PubMed Scopus (254) Google Scholar).Recent studies have identified two different ER-localized lectins that play a critical role in ERAD. The first is related to the mannosidase protein responsible for the trimming of N-glycans in the ER but appears to have lost its catalytic activity. In yeast it is called Htm1p/Mnl1p, and in mammals it is called EDEM (for ER degradation-enhancing α-mannosidase-like protein). Studies in mammalian cells suggest that EDEM helps misfolded glycoproteins leave the calnexin/calreticulin lectin chaperone cycle, where they are attempting to fold, and enter the degradation pathway (Molinari et al., 2003Molinari M. Calanca V. Galli C. Lucca P. Paganetti P. Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle.Science. 2003; 299: 1397-1400Crossref PubMed Scopus (384) Google Scholar, Oda et al., 2003Oda Y. Hosokawa N. Wada I. Nagata K. EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin.Science. 2003; 299: 1394-1397Crossref PubMed Scopus (383) Google Scholar). Nonetheless, in yeast, Htm1p is required for efficient degradation of substrates such as CPY∗ that do not depend on calnexin. Thus, it seems likely that Htm1p/EDEM plays other roles in ERAD. The second lectin, Yos9p, forms a stable complex with misfolded proteins, and loss of Yos9p leads to a profound and specific defect in degradation of misfolded glycoproteins (Cormier et al., 2005Cormier J.H. Pearse B.R. Hebert D.N. Yos9p: a sweet-toothed bouncer of the secretory pathway.Mol. Cell. 2005; 19: 717-719Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). Surprisingly, whereas point mutations in the Yos9p mannose binding pocket eliminate its ability to support ERAD, the same Yos9p mutants show enhanced interactions with substrates. This raises the intriguing (albeit speculative) possibility that the Yos9p lectin is playing a more informational role, querying the sugar status of misfolded forms to determine whether they should be passed on to the retrotranslocation machinery. However, as with ERAD-C, although there has been dramatic progress in characterizing the retrotranslocation machinery (Romisch, 2005Romisch K. Endoplasmic reticulum-associated degradation.Annu. Rev. Cell Dev. Biol. 2005; 21: 435-456Crossref PubMed Scopus (275) Google Scholar, Romisch, 2006Romisch K. Cdc48p is UBX-linked to ER ubiquitin ligases.Trends Biochem. Sci. 2006; 31: 24-25Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar), which structural features in misfolded proteins are being monitored and how the recognized misfolded forms are handed off to this machinery remain poorly understood.Aggregate Clearance via AutophagyIt has become increasingly apparent that there are a variety of conditions in vivo where, even with chaperones and the proteolytic machinery present in the same compartment as a misfolding protein, these mechanisms of quality control fail and the misfolded proteins proceed to form aggregates. Moreover, such intracellular aggregates are associated with a number of neurodegenerative diseases such as Huntington's and Parkinson's. The nature and fate of protein aggregates in eukaryotic cells has been poorly understood. Most recently, a protective action of aggregate formation, as opposed to an immediately pathogenic role, has been increasingly supported. For example, in the case of Huntington's disease, serial examination of neuronal cells in culture overproducing a polyglutamine-expanded huntingtin-GFP fusion revealed that those cells containing morphologically visible fluorescent aggregates exhibited better viability than those bearing diffusely fluorescent material (Arrasate et al., 2004Arrasate M. Mitra S. Schweitzer E.S. Segal M.R. Finkbeiner S. Inclusion body formation reduces levels of mutant huntingtin and risk of neuronal death.Nature. 2004; 431: 805-810Crossref PubMed Scopus (1584) Google Scholar). This seems consistent with the concept that it is small assemblies of misfolded proteins, not morphologically visible inclusions, that exert toxic effects on cells. Correspondingly, a recent comparison of size versus toxicity for aggregates of the prion protein PrP suggested that small aggregates containing one to two dozen molecules were the most toxic to cells (Silveira et al., 2005Silveira J.R. Raymond G.J. Hughson A.G. Race R.E. Sim V.L. Hayes S.F. Caughey B. The most infectious prion protein particles.Nature. 2005; 437: 257-261Crossref PubMed Scopus (748) Google Scholar). But do cells have mechanisms for clearing these small aggregates—or, for that matter, larger ones?Earlier studies suggested that the ubiquitin-proteasome pathway might be the mainstay of removal of aggregation-prone species. Indeed, aggregates detected in the setting of neurodegeneration are usually reactive with anti-ubiquitin antibodies, implying that the misfolding species have been recognized by the ubiquitin conjugation system. Yet evidence of the last few years indicates that these modified proteins present a particular challenge to proteasomes, possibly leading to their inhibition (Bence et al., 2001Bence N. Sampat R. Kopito R.R. Impairment of the ubiquitin-proteasome system by protein aggregation.Science. 2001; 292: 1552-1555Crossref PubMed Scopus (1796) Google Scholar, Bennett et al., 2005Bennett E.J. Bence N.F. Jayakumar R. Kopito R.R. Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation.Mol. Cell. 2005; 17: 351-365Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar). The mechanism of this inactivation remains unknown but may involve the “choking” of the proteasome chamber (Venkatraman et al., 2004Venkatraman P. Wetzel R. Tanaka M. Nukina N. Goldberg A.L. Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins.Mol. Cell. 2004; 14: 95-104Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar).It appears now that ubiquitin modification may in fact recruit aggregated species for clearance via an independent mechanism, the “autophagy” pathway. Autophagy involves the recognition and packaging/engulfment of targeted proteins or organelles into autophagosome vesicles that become fused with lysosomes, wherein both vesicles and their contents are broken down (Levine and Klionsky, 2004Levine B. Klionsky D.J. Development by self-digestion: Molecular mechanisms and biological functions of autophagy.Dev. Cell. 2004; 6: 463-477Abstract Full Text Full Text PDF PubMed Scopus (3139) Google Scholar). More than 20 so-called Atg components mediate this remarkable process. Recent experiments knocking out central components of autophagosome formation in mice have begun to demonstrate its scope of activity in mammalian tissues. For example, deficiency of atg5 led to death of newborn animals due to inability to provide a supply of amino acids via degradation of body protein during the relative starvation conditions of the immediate postnatal period (Kuma et al., 2004Kuma A. Hatano M. Matsui M. Yamamoto A. Nakaya H. Yoshimori T. Ohsumi Y. Tokuhisa T. Mizushima N. The role of autophagy during the early neonatal starvation period.Nature. 2004; 432: 1032-1036Crossref PubMed Scopus (2361) Google Scholar). Strikingly, in another study, in which atg7 deficiency was induced later in life using a “FLOXed” gene, accumulation of ubiquitin-positive aggregates was observed in the livers of animals that were disabled in the production of autophagosomes (Komatsu et al., 2005Komatsu M. Waguri S. Ueno T. Iwata J. Murata S. Tanida I. Ezaki J. Mizushima N. Ohsumi Y. Uchiyama Y. et al.Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice.J. Cell Biol. 2005; 169: 425-434Crossref PubMed Scopus (1882) Google Scholar). Proteasome function in such animals was unaffected, arguing that aggregates, containing misfolded ubiquitin-tagged species, may normally be removed by the autophagy pathway. Further insight into such a recruitment mechanism comes from studies in cultured cells expressing expanded GFP-huntingtin, which observed a component known as p62 (or sequestosome1) forming a “shell” around the huntingtin aggregates (Bjørkøy et al., 2005Bjørkøy G. Lamark T. Brech A. Outzen H. Perander M. Øvervatn A. Stenmark H. Johansen T. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death.J. Cell Biol. 2005; 171: 603-614Crossref PubMed Scopus (2462) Google Scholar). This protein contains a C-terminal ubiquitin-associated (UBA) domain that can bind polyubiquitin, such that p62 colocalized with ubiquitin when expressed in HeLa cells. Moreover, in the huntingtin-expressing cells, p62 colocalized with LC3, a protein that becomes localized to autophagosomes. Consistent with both reports showing that autophagy reduces levels of huntingtin aggregates (Ravikumar et al., 2004Ravikumar B. Vacher C. Berger Z. Davies J.E. Luo S. Oroz L.G. Scaravilli F. Easton D.F. Duden R. O'Kane C.J. Rubinsztein D.C. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease.Nat. Genet. 2004; 36: 585-595Crossref PubMed Scopus (1954) Google Scholar, Iwata et al., 2005Iwata A. Christianson J.C. Bucci M. Ellerby L.M. Nukina N. Forno L.S. Kopito R.R. Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation.Proc. Natl. Acad. Sci. USA. 2005; 102: 13135-13140Crossref PubMed Scopus (265) Google Scholar) and with a critical role of p62 in this process, antisense-mediated inhibition of p62 expression increased apoptosis of the huntingtin-expressing cells. Thus, it seems that ubiquitin modification of defective proteins may provide an entryway to either the proteasomal system or, in contexts where aggregation is occurring, the autophagy system.Hsp70 Chaperone Systems70 kDa heat-shock proteins (Hsp70s) are engaged in a plethora of folding processes including the folding of newly synthesized proteins, the transport of proteins across membranes, the refolding of misfolded and aggregated proteins, and the control of activity of regulatory proteins. This versatility is achieved through the evolutionary amplification and diversification of hsp70 genes, which has generated both specialized Hsp70 chaperones and more diverged Hsp110 and Hsp170 proteins. Versatility is also achieved through extensive employment of cochaperones, J proteins, and nucleotide exchange factors (NEFs), which regulate Hsp70 activity (see Figure 2). Recent studies have advanced our knowledge of the Hsp70 machine and its interactions with its cochaperones. Surprisingly, these studies have also uncovered functional liaisons between Hsp70s themselves.Figure 2Hsp70 InteractionsShow full captionLeft panel: Communication between the nucleotide binding domain (NBD, blue) and the substrate binding domain (SBD, yellow) of an Hsp70, as indicated from the crystal structure of bovine Hsc70 (Jiang et al., 2005Jiang J. Prasad K. Lafer E.M. Sousa R. Structural basis of interdomain communication in the Hsc70 chaperone.Mol. Cell. 2005; 20: 513-524Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar), featuring a 10 residue linker segment (purple) and an interaction between helix A, a few residues of the β sandwich in the SBD (both shown in red), and a groove in the NBD (green). Signal transduction from the catalytic center of the NBD to the interdomain interface is mediated by a hydrogen bond network with key residues (orange) being E175 as nucleotide sensor, P147 as structural switch, and R155 as surface-exposed relay (Vogel et al., 2006Vogel M. Bukau B. Mayer M.P. Allosteric regulation of Hsp70 chaperones by a proline switch.Mol. Cell. 2006; 21: 359-367Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar).Middle panel: The features of the Hsp70 cycle. NBD is shown in blue, SBD in yellow, and substrate protein in red. J proteins stimulate ATP hydrolysis, locking substrate into the SBD; NEF proteins exchange ATP for ADP, leading to substrate release.Right panel: The effects of Ssz1p, Lhs1p, and Sse1p on the Hsp70 cycle of three specific Hsp70 proteins, Ssb, Kar2p, and Ssa/Ssb, are indicated with arrows. e.g., Ssz1p in complex with zuotin (Zuo1p) stimulates ATP hydrolysis of Ssb (see text for additional detail).Inset panel: Interactions of nucleotide exchange factors (NEFs) with Hsp70 nucleotide binding domains are revealed by three cocrystal structures, showing a number of different ways in which NEF proteins contact the ATP binding domain to open up its cleft to enable nucleotide exchange. Ribbon diagrams of these structures are shown for DnaK-GrpE2 (Harrison et al., 1997Harrison C.J. Hayer-Hartl M. DiLiberto M. Hartl F.-U. Kuriyan J. Crystal structure of the nucleotide exchange factor GrpE bound to the ATPase domain of the molecular chaperone DnaK.Science. 1997; 276: 431-435Crossref PubMed Scopus (409) Google Scholar), Hsc70-Bag-1 (Sondermann et al., 2001Sondermann H. Scheufler C. Schneider C. Hohfeld J. Hartl F.U. Moarefi I. Structure of a Bag/Hsc70 complex: convergent functional evolution of Hsp70 nucleotide exchange factors.Science. 2001; 291: 1553-1557Crossref PubMed Scopus (360) Google Scholar), and Hsp70-HspBP1 (Shomura et al., 2005Shomura Y. Dragovic Z. Chang H.C. Tzvetkov N. Young J.C. Brodsky J.L. Guerriero V. Hartl F.U. Bracher A. Regulation of Hsp70 function by HspBP1: structural analysis reveals an alternate mechanism for Hsp70 nucleotide exchange.Mol. Cell. 2005; 17: 367-379Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar). At the right side of each ribbon diagram is a schematic showing how contacts between the NEFs and the NBDs serve to open the cleft between subdomains to enable nucleotide exchange.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Allosteric Crosstalk in Hsp70Hsp70s transiently associate with hydrophobic peptide stretches exposed in client proteins via a substrate binding domain (SBD) (Figure 2), thereby preventing aggregation and promoting proper folding. ATP binding to the N-terminal nucleotide binding domain (NBD) induces conformational changes in the adjacent SBD, which opens the substrate binding pocket and its helical lid (Figure 2). Conversely, substrate binding in synergy with the action of J proteins triggers ATP hydrolysis and concomitant closing of the SDB, which traps substrate proteins. Until recently, atomic structures were available only for the individual domains of Hsp70, which precluded a mechanistic understanding of interdomain communication. Sousa and coworkers have now solved the structure of bovine Hsc70 in a nucleotide-free state at 2.6 Å resolution. The structure (Figure 2) lacks only 10 kDa from the C terminus, leaving the substrate binding pocket intact (except the distal end of its helical lid) (Jiang et al., 2005Jiang J. Prasad K. Lafer E.M. Sousa R. Structural basis of interdomain communication in the Hsc70 chaperone.Mol. Cell. 2005; 20: 513-524Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). It had been shown from previously solved structures of isolated domains that the NBD consists of an actin-like fold with two globular subdomains separated by a nucleotide binding cleft whereas the SBD has a β sandwich that forms the substrate binding pocket, with an α-helix packed against the sandwich from one side (helix A) and a helical lid (helix B) closing on top of the substrate binding pocket. The new structure now reveals the elements providing the interdomain interaction, involving a flexible linker of 10 residues that connects the NBD and SBD; helix A of the SBD is embedded into a groove at the base of the NBD, and an additional contact is made between a few residues of the β sandwich of the SBD and the NBD groove (Figure 2). ATP binding may rearrange the interface between the NBD groove and SBD helix A, perhaps even disrupting it, thereby facilitating the opening of the SBD. Concomitantly, the linker may relocate and become more tightly associated with the connecting region, such that at no stage during the functional cycle of Hsp70 do the SBD and NBD become completely disconnected. It appears that the additional minor contact involving residues of the β sandwich of the SBD plays a critical role because a mutant with alteration in one of the involved residues has coupling defects (Montgomery et al., 1999Montgomery D.L. Morimoto R.I. Gierasch L.M. Mutations in the substrate binding domain of the Escherichia coli 70 kDa molecular chaperone DnaK which alter substrate affinity or interdomain coupling.J. Mol. Biol. 1999; 286: 915-932Crossref PubMed Scopus (128) Google Scholar). Signal transduction between SBD and NBD thus seems to rely on integrated rearrangements of the linker and at least two contact sites within the SBD.Progress has also been made concerning the mechanism by which the structural changes resulting from ATP binding and hydrolysis are transmitted within the NBD. A hydrogen bond network relays the conformational signal within the NBD of bacterial DnaK, starting at a glutama" @default.
• W2087689873 created "2016-06-24" @default.
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• W2087689873 date "2006-05-01" @default.
• W2087689873 modified "2023-10-18" @default.
• W2087689873 title "Molecular Chaperones and Protein Quality Control" @default.
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• W2087689873 doi "https://doi.org/10.1016/j.cell.2006.04.014" @default.
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