Hierarchical dynamics in allostery following ATP hydrolysis monitored by single molecule FRET measurements and MD simulations

Wolf, Steffen; Sohmen, Benedikt; Hellenkamp, Björn; Thurn, Johann; Stock, Gerhard; Hugel, Thorsten

doi:10.1039/d0sc06134d

Cited by 29 publications

(43 citation statements)

References 59 publications

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“…Three conformational states can be distinguished by FRET efficiency E vs. stoichiometry analysis S: An open state at E ∼0.13, a closed state at E ∼0.63 and a more contracted closed state at E ∼0.85. This is consistent with previous results [43] and with the proximity ratios obtained in Fig. 2.…”

Section: Separating Rotation From Internal Dynamics By Time-resolved ...supporting

confidence: 94%

“…We access a complex pattern of diffusive modes, which can be described with our integrative approach covering a wide range of time and length scales. Overall, together with the previously published dynamics on slower time scales [19,43,44] our results complete a comprehensive picture of Hsp90's dynamics from the nanosecond to second time scale and show that even the fastest dynamics is relevant for the molecular regulation mechanism controlled by an interacting protein.…”

Section: Introductionsupporting

confidence: 81%

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The onset of molecule-spanning dynamics in a multi-domain protein

Sohmen¹,

Beck²,

Seydel³

et al. 2021

Preprint

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A complete understanding of protein function requires not only structural, but also dynamical information on a wide range of time scales. Large proteins present a particular challenge for nanosecond dynamics, as a comprehensive experimental investigation and an associated multi-scale understanding of how dynamics leads to function has not been established so far. In this study we not only determine these nanosecond dynamics for the multi-domain chaperone protein Hsp90, but also assign them to real-space movements and 1

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Section: Separating Rotation From Internal Dynamics By Time-resolved ...supporting

confidence: 94%

Section: Introductionsupporting

confidence: 81%

The onset of molecule-spanning dynamics in a multi-domain protein

Sohmen¹,

Beck²,

Seydel³

et al. 2021

Preprint

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“…Moreover, the above described lever-arm effect is reminiscent of structural changes in G protein-coupled receptors, where small changes in the ligand binding site are structurally amplified to large-scale protein surface changes at the G protein binding site 37,38 . A similar effect was also reported for the microbial rhodopsin bacteriorhodopsin, where the retinal cofactor pushing against Trp182 causes a large-scale outward motion of helix F 39 , and for the connection between ATP hydrolysis and protein conformational changes in heat shock protein 90 17 . The interplay between rigid secondary elements (such as α-helices and β-sheets) and flexible protein sections (such as loops or linkers) to mediate structural rearrangements was also discussed by Nussinov and Thirumalai 6,40 .…”

Section: Discussionsupporting

confidence: 73%

Cooperative protein allosteric transition mediated by a fluctuating transmission network

Post

Lickert

Diez

et al. 2021

Preprint

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Allosteric communication between distant protein sites represents a key mechanism of biomolecular regulation and signal transduction. Compared to other processes such as protein folding, however, the dynamical evolution of allosteric transitions is still not well understood. As example of allosteric coupling between distant protein regions, we consider the global open-closed motion of the two domains of T4 lysozyme, which is triggered by local motions in the hinge region. Combining extensive molecular dynamics simulations with machine learning of contact features, we identify a network of interresidue distances that move in a concerted manner. The cooperative process originates from a cogwheel-like motion of the hydrophobic core in the hinge region, which constitutes a flexible transmission network. Through rigid contacts and the protein backbone, the small local changes of the hydrophobic core are passed on to the distant terminal domains and lead to the emergence of a rare global conformational transition. As in an Ising-type model, the cooperativity of the allosteric transition can be explained via the interaction of local fluctuations.

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“…Similarly, two closed conformations have been detected for cytosolic Hsp90 from bulk FRET, smFRET, and electron paramagnetic resonance measurements ( 31 – 33 ). These alternative closed structures are not known with certainty, but one has been proposed from smFRET measurements ( 34 ), and a recent report shows cytosolic Hsp90 in a semiclosed conformation when in complex with Hsp70, Hop, and the glucocorticoid receptor ( 16 ). Structural studies of Trap1 (the mitochondria-specific Hsp90 paralog) have also identified different closed conformations that are distinct from the well-established closed conformations of cytosolic Hsp90 and Grp94.…”

mentioning

confidence: 99%

The endoplasmic reticulum chaperone BiP is a closure-accelerating cochaperone of Grp94

Huang

Sun

Hoxie

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Hsp70 and Hsp90 chaperones provide protein quality control to the cytoplasm, endoplasmic reticulum (ER), and mitochondria. Hsp90 activity is often enhanced by cochaperones that drive conformational changes needed for ATP-dependent closure and capture of client proteins. Hsp90 activity is also enhanced when working with Hsp70, but, in this case, the underlying mechanistic explanation is poorly understood. Here we examine the ER-specific Hsp70/Hsp90 paralogs (BiP/Grp94) and discover that BiP itself acts as a cochaperone that accelerates Grp94 closure. The BiP nucleotide binding domain, which interacts with the Grp94 middle domain, is responsible for Grp94 closure acceleration. A client protein initiates a coordinated progression of steps for the BiP/Grp94 system, in which client binding to BiP causes a conformational change that enables BiP to bind to Grp94 and accelerate its ATP-dependent closure. Single-molecule fluorescence resonance energy transfer measurements show that BiP accelerates Grp94 closure by stabilizing a high-energy conformational intermediate that otherwise acts as an energetic barrier to closure. These findings provide an explanation for enhanced activity of BiP and Grp94 when working as a pair, and demonstrate the importance of a high-energy conformational state in controlling the timing of the Grp94 conformational cycle. Given the high conservation of the Hsp70/Hsp90 system, other Hsp70s may also serve dual roles as both chaperones and closure-accelerating cochaperones to their Hsp90 counterparts.

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Hierarchical dynamics in allostery following ATP hydrolysis monitored by single molecule FRET measurements and MD simulations

Abstract: We report on a study that combines advanced fluorescence methods with molecular dynamics simulations to cover timescales from nanoseconds to milliseconds for a large protein, the chaperone Hsp90.

Cited by 29 publications

References 59 publications

The onset of molecule-spanning dynamics in a multi-domain protein

The onset of molecule-spanning dynamics in a multi-domain protein

Cooperative protein allosteric transition mediated by a fluctuating transmission network

The endoplasmic reticulum chaperone BiP is a closure-accelerating cochaperone of Grp94

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