Arthur L Horwich

Yale University | YU · Boyer Center for Molecular Medicine

A recent hydrogen-deuterium exchange study of folding of the GroEL/GroES-dependent bacterial enzyme DapA has suggested that the DapA folding pathway when free in solution may differ from the folding pathway used in the presence of the GroEL/GroES chaperonin. Here, we have investigated whether DapA aggregation might be occurring in free solution und...

Significance We describe a method that allows, for the first time to our knowledge, the preparation of viable acute spinal cord slices from adult mice, enabling patch-clamp recording from fluorescent motor neurons. From electrophysiological parameters, four subtypes of motor neurons were identified. Two fast firing subtypes innervated fast twitch m...

Significance This is the first report, to our knowledge, of the absence of lipofuscin, “aging pigment,” in a setting of motor neuron neurodegenerative disease, mutant SOD1-linked ALS. Although the initial hypothesis was that this must be due to a block in the autophagy/lysosome pathway, instead studies of autophagy markers and of ALS mice treated w...

The early decades of Cell witnessed key discoveries that coalesced into the field of chaperones, protein folding, and protein quality control.

Preparation of high-quality RNA from cells of interest is critical to precise and meaningful analysis of transcriptional differences among cell types or between the same cell type in health and disease or following pharmacologic treatments. In the spinal cord, such preparation from motor neurons, the target of interest in many neurologic and neurod...

We have been studying chaperonins these past twenty years through an initial discovery of an action in protein folding, analysis of structure, and elucidation of mechanism. Some of the highlights of these studies were presented recently upon sharing the honor of the 2013 Herbert Tabor Award with my early collaborator, Ulrich Hartl, at the annual me...

Mutant human Cu/Zn superoxide dismutase 1 (SOD1) is associated with motor neuron toxicity and death in an inherited form of amyotrophic lateral sclerosis (ALS; Lou Gehrig disease). One aspect of toxicity in motor neurons involves diminished fast axonal transport, observed both in transgenic mice and, more recently, in axoplasm isolated from squid g...

Ubiquitin C-terminal hydrolase-L1 (UCHL1), a neuron-specific de-ubiquitinating enzyme, is one of the most abundant proteins in the brain. We describe three siblings from a consanguineous union with a previously unreported early-onset progressive neurodegenerative syndrome featuring childhood onset blindness, cerebellar ataxia, nystagmus, dorsal col...

Mechanisms involved with degeneration of motor neurons in amyotrophic lateral sclerosis (ALS; Lou Gehrig's Disease) are poorly understood, but genetically inherited forms, comprising ∼10% of the cases, are potentially informative. Recent observations that several inherited forms of ALS involve the RNA binding proteins TDP43 and FUS raise the questi...

Chaperonins are intricate allosteric machines formed of two back-to-back, stacked rings of subunits presenting end cavities lined with hydrophobic binding sites for nonnative polypeptides. Once bound, substrates are subjected to forceful, concerted movements that result in their ejection from the binding surface and simultaneous encapsulation insid...

The chaperonin GroEL assists the folding of nascent or stress-denatured polypeptides by actions of binding and encapsulation. ATP binding initiates a series of conformational changes triggering the association of the cochaperonin GroES, followed by further large movements that eject the substrate polypeptide from hydrophobic binding sites into a Gr...

Mutations of cytosolic Cu/Zn superoxide dismutase 1 (SOD1) in humans and overexpression of mutant human SOD1 genes in transgenic mice are associated with the motor neuron degenerative condition known as amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease). Gain-of-function toxicity from the mutant protein expressed in motor neurons, associated...

In structural biology, pulsed field gradient (PFG) NMR spectroscopy for the characterization of size and hydrodynamic parameters of macromolecular solutes has the advantage over other techniques that the measurements can be recorded with identical solution conditions as used for NMR structure determination or for crystallization trials. This paper...

The molecular chaperone GroEL is required for bacterial growth under all conditions, mediating folding assistance, via its central cavity, to a diverse set of cytosolic proteins; yet the subcellular localization of GroEL remains unresolved. An earlier study, using antibody probing of fixed Escherichia coli cells, indicated colocalization with the c...

Nuclear magnetic resonance (NMR) observation of the uniformly (2) H,(15) N-labeled stringent 33-kDa substrate protein rhodanese in a productive complex with the uniformly (14) N-labeled 400 kDa single-ring version of the E. coli chaperonin GroEL, SR1, was achieved with the use of transverse relaxation-optimized spectroscopy, cross-correlated relaxa...

Under "permissive" conditions at 25°C, the chaperonin substrate protein DM-MBP refolds 5-10 times more rapidly in the GroEL/GroES folding chamber than in free solution. This has been suggested to indicate that the chaperonin accelerates polypeptide folding by entropic effects of close confinement. Here, using native-purified DM-MBP, we show that th...

The GroEL/GroES protein folding chamber is formed and dissociated by ATP binding and hydrolysis. ATP hydrolysis in the GroES-bound (cis) ring gates entry of ATP into the opposite unoccupied trans ring, which allosterically ejects cis ligands. While earlier studies suggested that hydrolysis of cis ATP is the rate-limiting step of the cycle (t1/2 app...

The GroEL/GroES reaction cycle involves steps of ATP and polypeptide binding to an open GroEL ring before the GroES encapsulation step that triggers productive folding in a sequestered chamber. The physiological order of addition of ATP and nonnative polypeptide, typically to the open trans ring of an asymmetrical GroEL/GroES/ADP complex, has been...

The GroEL/GroES chaperonin folding chamber is an encapsulated space of approximately 65 A diameter with a hydrophilic wall, inside of which many cellular proteins reach the native state. The question of whether the cavity wall actively directs folding reactions or is playing a passive role has been open. We review past and recent observations and c...

The chaperonin ring assembly GroEL provides kinetic assistance to protein folding in the cell by binding non-native protein in the hydrophobic central cavity of an open ring and subsequently, upon binding ATP and the co-chaperonin GroES to the same ring, releasing polypeptide into a now hydrophilic encapsulated cavity where productive folding occur...

The chaperonin GroEL is a megadalton-sized molecular machine that plays an essential role in the bacterial cell assisting protein folding to the native state through actions requiring ATP binding and hydrolysis. A combination of medicinal chemistry and genetics has been employed to generate an orthogonal pair, a small molecule that selectively inhi...

The nature of toxic effects exerted on neurons by misfolded proteins, occurring in a number of neurodegenerative diseases, is poorly understood. One approach to this problem is to measure effects when such proteins are expressed in heterologous neurons. We report on effects of an ALS-associated, misfolding-prone mutant human SOD1, G85R, when expres...

Recent studies suggest that superoxide dismutase 1 (SOD1)-linked amyotrophic lateral sclerosis results from destabilization and misfolding of mutant forms of this abundant cytosolic enzyme. Here, we have tracked the expression and fate of a misfolding-prone human SOD1, G85R, fused to YFP, in a line of transgenic G85R SOD1-YFP mice. These mice, but...

Production of the folding-active state of a GroEL ring involves initial cooperative binding of ATP, recruiting GroES, followed by large rigid body movements that are associated with ejection of bound substrate protein into the encapsulated hydrophilic chamber where folding commences. Here, we have addressed how many of the 7 subunits of a GroEL rin...

The original experiments reconstituting GroEL–GroES-mediated protein folding were carried out under “nonpermissive” conditions, where the chaperonin system was absolutely required and substrate proteins could not achieve the native state if diluted directly from denaturant into solution. Under “permissive” conditions, however, employing lower subst...

Chaperonin action is controlled by cycles of nucleotide binding and hydrolysis. Here, we examine the effects of nucleotide binding on an archaeal group 2 chaperonin. In contrast to the ordered apo state of the group 1 chaperonin GroEL, the unliganded form of the homo-16-mer Methanococcus maripaludis group 2 chaperonin is very open and flexible, wit...

I. Architecture of GroEL and GroES and the reaction pathway A. Architecture of the chaperonins B. Reaction pathway of GroEL-GroES-mediated folding II. Polypeptide binding A. A parallel network of chaperones binding polypeptides in vivo B. Polypeptide binding in vitro 1. Role of hydrophobicity in recognition 2. Homologous proteins with differing rec...

The chaperonin GroEL binds non-native polypeptides in an open ring via hydrophobic contacts and then, after ATP and GroES binding to the same ring as polypeptide, mediates productive folding in the now hydrophilic, encapsulated cis chamber. The nature of the folding reaction in the cis cavity remains poorly understood. In particular, it is unclear...

The chaperonin GroEL assists polypeptide folding through sequential steps of binding nonnative protein in the central cavity of an open ring, via hydrophobic surfaces of its apical domains, followed by encapsulation in a hydrophilic cavity. To examine the binding state, we have classified a large data set of GroEL binary complexes with nonnative ma...

Folding of substrate proteins inside the sequestered and hydrophilic GroEL-GroES cis cavity favors production of the native state. Recent studies of GroEL molecules containing volume-occupying multiplications of the flexible C-terminal tail segments have been interpreted to indicate that close confinement of substrate proteins in the cavity optimiz...

The chaperonin GroEL assists protein folding by binding nonnative forms through exposed hydrophobic surfaces in an open ring and mediating productive folding in an encapsulated hydrophilic chamber formed when it binds GroES. Little is known about the topology of nonnative proteins during folding inside the GroEL–GroES cis chamber. Here, we have mon...

Chaperonins are large ring assemblies that assist protein folding to the native state by binding nonnative proteins in their central cavities and then, upon binding ATP, release the substrate protein into a now-encapsulated cavity to fold productively. Two families of such components have been identified: type I in mitochondria, chloroplasts, and t...

In a newly isolated temperature-sensitive lethal Escherichia coli mutant affecting the chaperonin GroEL, we observed wholesale aggregation of newly translated proteins. After temperature shift, transcription, translation, and growth slowed over two to three generations, accompanied by filamentation and accretion (in ≈2% of cells) of paracrystalline...

The use of 1H-1H nuclear Overhauser effects (NOE) for structural studies of uniformly deuterated polypeptide chains in large structures is investigated by model calculations and NMR experiments. Detailed analysis of the evolution of the magnetization during 1H-1H NOE experiments under slow-motion conditions shows that the maximal 1H-1H NOE transfer...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

A review of the mechanism of protein refolding by GroEL-GroES machine is presented. Topics discussed include: chaperonins, specifically the establishment of a role on mediating protein folding in the cell; structural states of GroEL and the GroEL-GroES reaction cycle; and triggering productive folding. Under the second topic, focus is on the archit...

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 mechanism...

The double-ring chaperonin GroEL and its lid-like cochaperonin GroES form asymmetric complexes that, in the ATP-bound state, mediate productive folding in a hydrophilic, GroES-encapsulated chamber, the so-called cis cavity. Upon ATP hydrolysis within the cis ring, the asymmetric complex becomes able to accept non-native polypeptides and ATP in the...

The hexameric cylindrical Hsp100 chaperone ClpA mediates ATP-dependent unfolding and translocation of recognized substrate proteins into the coaxially associated serine protease ClpP. Each subunit of ClpA is composed of an N-terminal domain of approximately 150 amino acids at the top of the cylinder followed by two AAA+ domains. In earlier studies,...

The reaction cycle and the major structural states of the molecular chaperone GroEL and its cochaperone, GroES, are well characterized. In contrast, very little is known about the nonnative states of the substrate polypeptide acted on by the chaperonin machinery. In this study, we investigated the substrate protein human dihydrofolate reductase (hD...

The cylindrical Hsp100 chaperone ClpA mediates ATP-dependent unfolding of substrate proteins bearing "tag" sequences, such as the 11-residue ssrA sequence appended to proteins translationally stalled at ribosomes. Unfolding is coupled to translocation through a central channel into the associating protease, ClpP. To explore the topology and mechani...

In tritium-hydrogen exchange experiments, the large GroEL substrate Rubisco was unfolded and exchanged in urea/acid/tritiated water, then diluted into either protic buffer or protic buffer containing GroEL. The respective Rubisco metastable folding intermediate or Rubisco-GroEL binary complex was then separated from residual tritium after varying t...

In this issue of Cell, exploit a clever manipulation of the Hsp100 ring chaperone, ClpB, to gain some mechanistic and physiologic understanding of the action of this chaperone in mediating ATP-dependent disaggregation of protein aggregates that accumulate in the bacterial cytoplasm under severe heat shock conditions.

The chaperonin GroEL assists protein folding through ATP-dependent, cooperative movements that alternately create folding chambers in its two rings. The substitution E461K at the interface between these two rings causes temperature-sensitive, defective protein folding in Escherichia coli. To understand the molecular defect, we have examined the mut...

A conundrum has arisen in the study of the structural states of the GroEL-GroES chaperonin machine: When either ATP or ADP is added along with GroES to GroEL, the same asymmetric complex, with one ring in a GroES-domed state, is observed by either x-ray crystallographic study or cryoelectron microscopy. Yet only ATP/GroES can trigger productive fol...

A conundrum has arisen in the study of the structural states of the GroEL-GroES chaperonin machine: When either ATP or ADP is added along with GroES to GroEL, the same asymmetric complex, with one ring in a GroES-domed state, is observed by either x-ray crystallographic study or cryoelectron microscopy. Yet only ATP/GroES can trigger productive fol...

A chaperone molecule called trigger factor binds new polypeptide chains as they emerge from the protein-synthesis machinery. Crystal structures suggest that this molecule forms a hydrophobic 'cradle'.

Large rigid-body domain movements are critical to GroEL-mediated protein folding, especially apical domain elevation and twist associated with the formation of a folding chamber upon binding ATP and co-chaperonin GroES. Here, we have modeled the anisotropic displacements of GroEL domains from various crystallized states, unliganded GroEL, ATPgammaS...

A general method for stable-isotope labeling of large proteins is introduced and applied for studies of the E. coli GroE chaperone proteins by solution NMR. In addition to enabling the residue-specific (15)N-labeling of proteins on a highly deuterated background, it is also an efficient approach for uniform labeling. The method meets the requiremen...

A chaperone molecule called trigger factor binds new polypeptide chains as they emerge from the protein-synthesis machinery. Crystal structures suggest that this molecule forms a hydrophobic ‘cradle’.

This chapter discusses the role of adenosine triphosphate (ATP) in directing chaperonin-mediated polypeptide folding. Despite its relative inefficiency, the action of ATP is essential to the chaperonin reaction. In the absence of ATP, while chaperonin is still able to bind a nonnative substrate protein, polypeptide folding and ejection do not follo...

Productive cis folding by the chaperonin GroEL is triggered by the binding of ATP but not ADP, along with cochaperonin GroES, to the same ring as non-native polypeptide, ejecting polypeptide into an encapsulated hydrophilic chamber. We examined the specific contribution of the -phosphate of ATP to this activation process using complexes of ADP and...

Although a cis mechanism of GroEL-mediated protein folding, occurring inside a hydrophilic chamber encapsulated by the co-chaperonin GroES, has been well documented, recently the GroEL–GroES-mediated folding of aconitase, a large protein (82 kDa) that could not be encapsulated, was described. This process required GroES binding to the ring opposite...

1. Chaperonin action – an overview 230 2. Polypeptide binding – an essential action 235 3. Recognition of non-native polypeptide – role of hydrophobicity 236 4. Crystallographic analyses of peptide binding 237 5. Topology and secondary and tertiary structure of bound substrate polypeptide – fluorescence, hydrogen exchange and NMR studies 239 6. Bin...

Transverse relaxation-optimized spectroscopy (TROSY) or generation of heteronuclear multiple quantum coherences during the frequency labeling period and TROSY during the acquisition period have been combined either with cross-correlated relaxation-induced polarization transfer (CRIPT) or cross-correlated relaxation-enhanced polarization transfer (C...

Biomacromolecular structures with a relative molecular mass (M(r)) of 50,000 to 100,000 (50K 100K) have been generally considered to be inaccessible to analysis by solution NMR spectroscopy. Here we report spectra recorded from bacterial chaperonin complexes ten times this size limit (up to M(r) 900K) using the techniques of transverse relaxation-o...

In the bacterial cytosol, ATP-dependent protein degradation is performed by several different chaperone-protease pairs, including ClpAP. The mechanism by which these machines specifically recognize substrates remains unclear. Here, we report the identification of a ClpA cofactor from Escherichia coli, ClpS, which directly influences the ClpAP machi...

The chaperonin GroEL drives its protein-folding cycle by cooperatively binding ATP to one of its two rings, priming that ring to become folding-active upon GroES binding, while simultaneously discharging the previous folding chamber from the opposite ring. The GroEL-ATP structure, determined by cryo-EM and atomic structure fitting, shows that the i...

The chaperonin GroEL binds nonnative proteins too large to fit inside the productive GroEL-GroES cis cavity, but whether and how it assists their folding has remained unanswered. We have examined yeast mitochondrial aconitase, an 82 kDa monomeric Fe(4)S(4) cluster-containing enzyme, observed to aggregate in chaperonin-deficient mitochondria. We obs...

The chaperonin GroEL binds nonnative substrate protein in the hydrophobic central cavity of an open ring. ATP and GroES binding to the same ring converts this cavity into an encapsulated, hydrophilic chamber that mediates productive folding. A 'rack' mechanism of initial protein unfolding proposes that, upon GroES and ATP binding, the polypeptide i...

The intracellular degradation of many proteins is mediated in an ATP-dependent manner by large assemblies comprising a chaperone ring complex associated coaxially with a proteolytic cylinder, e.g., ClpAP, ClpXP, and HslUV in prokaryotes, and the 26S proteasome in eukaryotes. Recent studies of the chaperone ClpA indicate that it mediates ATP-depende...

The strong correlation between protein folding rates and the contact order suggests that folding rates are largely determined by the topology of the native structure. However, for a given topology, there may be several possible low free energy paths to the native state and the path that is chosen (the lowest free energy path) may depend on differen...

Chaperonins are large, double-ring complexes that assist the folding to native form of a wide variety of proteins in the cytosol of all cells and in mitochondria and chloroplasts of eukaryotes. Advances in structural biology are revealing additional states of the chaperonin machine that represent essential steps in the protein folding reaction. At...

The chaperonin GroEL binds nonnative substrate protein in the central cavity of an open ring through exposed hydrophobic residues at the inside aspect of the apical domains and then mediates productive folding upon binding ATP and the cochaperonin GroES. Whether nonnative proteins bind to more than one of the seven apical domains of a GroEL ring is...

Chaperone rings play a vital role in the opposing ATP-mediated processes of folding and degradation of many cellular proteins, but the mechanisms by which they assist these life and death actions are only beginning to be understood. Ring structures present an advantage to both processes, providing for compartmentalization of the substrate protein i...

The bacterial protein CIpA, a member of the Hsp100 chaperone family, forms hexameric rings that bind to the free ends of the double-ring serine protease ClpP. ClpA directs the ATP-dependent degradation of substrate proteins bearing specific sequences, much as the 19S ATPase 'cap' of eukaryotic proteasomes functions in the degradation of ubiquitinat...

The double-ring chaperonin GroEL mediates protein folding in the central cavity of a ring bound by ATP and GroES, but it is unclear how GroEL cycles from one folding-active complex to the next. We observe that hydrolysis of ATP within the cis ring must occur before either nonnative polypeptide or GroES can bind to the trans ring, and this is associ...

Cyclin E, a partner of the cyclin-dependent kinase Cdk2, has been implicated in positive control of the G 1 /S phase transition. Whereas degradation of cyclin E has been shown to be exquisitely regulated by ubiquitination and proteasomal action, little is known about posttranscriptional aspects of its biogenesis. In a yeast-based screen designed to...

The chapter presents a study related to the construction of single-ring and two-ring hybrid versions of bacterial chaperonin GroEL. A single-ring version of the bacterial chaperonin, GroEL, has been designed using information from the crystal structure of the native double-ring assembly. This molecule, designated SR1, has proved to be functional as...

The nature of chaperone action in the eukaryotic cytosol that assists newly translated cytosolic proteins to reach the native state has remained poorly defined. Actin, tubulin, and Galpha transducin are assisted by the cytosolic chaperonin, CCT, but many other proteins, for example, ornithine transcarbamoylase (OTC), a cytosolic homotrimeric enzyme...

Recent crystal structures of the Thermoplasma acidophilum thermosome and its isolated apical domain suggest that an integral extension of the apical domain encloses the folding-active chaperonin central cavity.

B. B. thanks members of his lab and J. Reinstein for critical reading of the manuscript and C. Gassler, T. Laufen, and S. Rudiger for figure preparation. A. H. thanks Wayne Fenton for critical reading and Zhaohui Xu for figure preparation. A. H. dedicates this work to Guenter Brueckner, always an inspiration.

Recent structural and biochemical investigations have come together to allow a better understanding of the mechanism of chaperonin (GroEL, Hsp60)-mediated protein folding, the final step in the accurate expression of genetic information. Major, asymmetric conformational changes in the GroEL double toroid accompany binding of ATP and the cochaperoni...

Chaperonin 60, cpn60 (Hemmingsen et al., 1988; Goloubinoff etal., 1989b); GroES as chaperonin 10, cpn10 (Goloubinoff etal., 1989a). GroEL was originally identified through mutations of Escherichia coli that led to defective A phage biogenesis (Georgopoulos et al., 1973; Sternberg, 1973).

Chaperonins assist protein folding with the consumption of ATP. They exist as multi-subunit protein assemblies comprising rings of subunits stacked back to back. In Escherichia coli, asymmetric intermediates of GroEL are formed with the co-chaperonin GroES and nucleotides bound only to one of the seven-subunit rings (the cis ring) and not to the op...

The chaperonin GroEL is a double-ring structure with a central cavity in each ring that provides an environment for the efficient folding of proteins when capped by the co-chaperone GroES in the presence of adenine nucleotides. Productive folding of the substrate rhodanese has been observed in cis ternary complexes, where GroES and polypeptide are...

The eukaryotic cytosolic chaperonin, CCT, plays an essential role in mediating ATP-dependent folding of actin and tubulin. There is debate about whether it mediates folding through a single round of association followed by release of native forms, or through cycles of binding and full release in which only a fraction of released molecules reaches n...

Novel infectious particles, termed prions, composed largely and perhaps solely of a single protein, are the likely causative agents of a group of transmissible spongiform encephalopathies that produce lethal decline of cognitive and motor function. As if the notion of a transmissible pathogenic protein is not jarring enough, evidence indicates that...

The chaperonin GroEL binds nonnative proteins in its central channel through hydrophobic interactions and initiates productive folding in this space underneath bound co-chaperone, GroES, in the presence of ATP. The questions of where along the folding pathway a protein is recognized by GroEL, and how much structure is present in a bound substrate h...

This chapter discusses the structure and function of chaperonins in archaebacteria. It is possible that chaperonin-containing TCP-1 (CCT) evolved solely to cope with the folding of a few cytoskeletal proteins such as actin and tubulin, and that it represents a special, unusual type of chaperonin that is able to do useful tasks for the folding probl...

Protein folding by the double-ring chaperonin GroEL is initiated in cis ternary complexes, in which polypeptide is sequestered in the central channel of a GroEL ring, capped by the co-chaperonin GroES. The cis ternary complex is dissociated (half-life of approximately 15 s) by trans-sided ATP hydrolysis, which triggers release of GroES. For the sub...

The co-chaperonin GroES is an essential partner in protein folding mediated by the chaperonin, GroEL. Two recent crystal structures of GroES provide a structural basis to understand how GroES forms the lid on the folding-active cis ternary complex, and how the GroEL-GroES complex enhances folding.

Inherited single gene defects have been identified in both mice and humans that result in the loss of control over the development of left-right asymmetry of the heart and viscera. In mice, the recessively inheritediv (inversus viscerum) mutation results in randomization of left-right asymmetry: 50% of homozygous, live-born iv mice have situs solit...

Recent studies of GroE-mediated protein folding indicate that substrate proteins are productively released from a cis ternary complex in which the nonnative substrate is sequestered within the GroEL channel underneath GroES. Here, we examine whether protein folding can occur in this space. Stopped-flow fluorescence anisotropy of a pyrene-rhodanese-...

GroEL is a bacterial chaperonin of 14 identical subunits required to help fold newly synthesized proteins. The crystal structure of GroEL with ATP gamma S bound to each subunit shows that ATP binds to a novel pocket, whose primary sequence is highly conserved among chaperonins. Interaction of Mg2+ and ATP involves phosphate oxygens of the alpha-, b...

The chaperonin GroEL is a large, double-ring structure that, together with ATP and the cochaperonin GroES, assists protein folding in vivo. GroES forms an asymmetric complex with GroEL in which a single GroES ring binds one end of the GroEL cylinder. Cross-linking studies reveal that polypeptide binding occurs exclusively to the GroEL ring not occu...

Recent studies implicate Hsp104/Clp family chaperones in both protein disaggregation and protein degradation. How do these homologous ring-shaped complexes function in such different ways?