Chaperone-client interactions: Non-specificity engenders multifunctionality

Koldewey, Philipp; Horowitz, Scott; Bardwell, James C.A.

doi:10.1074/jbc.r117.796862

Cited by 66 publications

(49 citation statements)

References 101 publications

(141 reference statements)

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“…Our study demonstrates that the unique structural property of NMNAT gives rise to the binding of pTau with a high affinity comparable to that of an enzyme-substrate binding, but distinct from the weak interaction commonly found in chaperone-client binding (Koldewey, Horowitz, & Bardwell, 2017). The co-existence of the NAD synthase and chaperone activity sharing a common surface of NMNAT indicates an evolutionary connection between NAD metabolism and Tau proteostasis.…”

Section: Nmnat Links Nad and Tau Metabolismmentioning

confidence: 70%

Mechanistic insights into NAD synthase NMNAT chaperoning phosphorylated Tau from pathological aggregation

Xie

et al. 2019

Preprint

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Tau hyper-phosphorylation and deposition into neurofibrillary tangles have been found in brains of patients with Alzheimer's disease (AD) and other tauopathies. Molecular chaperones are involved in regulating the pathological aggregation of phosphorylated Tau (pTau) and modulating disease progression. Here, we report that nicotinamide mononucleotide adenylyltransferase (NMNAT), a well-known NAD synthase, serves as a chaperone of pTau to prevent its amyloid aggregation in vitro as well as mitigate its pathology in a fly tauopathy model. By combining NMR spectroscopy, crystallography, single-molecule and computational approaches, we revealed that NMNAT adopts its enzymatic pocket to specifically bind the phosphorylated sites of pTau, which can be competitively disrupted by the enzymatic substrates of NMNAT.Moreover, we found that NMNAT serves as a co-chaperone of Hsp90 for the specific recognition of pTau over Tau. Our work uncovers a dedicated chaperone of pTau and suggests NMNAT as a key node between NAD metabolism and Tau homeostasis in aging and neurodegeneration.

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Section: Nmnat Links Nad and Tau Metabolismmentioning

confidence: 70%

Mechanistic insights into NAD synthase NMNAT chaperoning phosphorylated Tau from pathological aggregation

Xie

et al. 2019

Preprint

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“…Previous studies mainly focused on the molecular mechanism underlying the disaggregase activity of HSP104 (11,29,30,38), whereas in this study, we found that HSP104 can perform as a holdase to bind the soluble form of amyloid clients and prevent them from aggregation. Several chaperones have been reported to possess more than one chaperone activity (39). For example, HSP70 exhibits holdase, foldase, and disaggregase activities (39,40).…”

Section: Discussionmentioning

confidence: 99%

“…Several chaperones have been reported to possess more than one chaperone activity (39). For example, HSP70 exhibits holdase, foldase, and disaggregase activities (39,40). However, HSP70 utilizes a similar client recognition mechanism for different chaperone activities (41,42).…”

Section: Discussionmentioning

confidence: 99%

Heat shock protein 104 (HSP104) chaperones soluble Tau via a mechanism distinct from its disaggregase activity

Zhang

et al. 2019

Journal of Biological Chemistry

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Heat shock protein 104 (HSP104) is a conserved AAA؉ protein disaggregase, can disassemble the toxic aggregates formed by different amyloid proteins, and is protective in various animal models associated with amyloid-related diseases. Extensive studies have attempted to elucidate how HSP104 disassembles the aggregated form of clients. Here, we found that HSP104 exhibits a potent holdase activity that does not require energy, prevents the soluble form of amyloid clients from aggregating, and differs from HSP104's disaggregase activity. Using cryo-EM, NMR, and additional biophysical approaches, we found that HSP104 utilizes its small subdomain of nucleotide-binding domain 2 (ssNBD2) to capture the soluble amyloid client (K19 of Tau) independent of its ATP hydrolysis activity. Our results indicate that HSP104 utilizes two fundamental distinct mechanisms to chaperone different forms of amyloid client and highlight the important yet previously unappreciated function of ssNBD2 in chaperoning amyloid client and thereby preventing pathological aggregation.

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“…Frustrated regions in folding simulations may be identified using the Frustratometer (101,148), again allowing the identification of possible accessible recognition sites in the conformational ensembles of likely long-lived folding intermediates. Although these proposed methods are relatively primitive and not applicable to all chaperones (149), they have the potential to provide structural information on transient folding intermediates that may be recognized by chaperone networks.…”

Section: Extrapolating From Folding Simulations To Folding In More Comentioning

confidence: 99%

Successes and challenges in simulating the folding of large proteins

Gershenson

Gosavi

Faccioli

et al. 2020

Journal of Biological Chemistry

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Computational simulations of protein folding can be used to interpret experimental folding results, to design new folding experiments, and to test the effects of mutations and small molecules on folding. However, whereas major experimental and computational progress has been made in understanding how small proteins fold, research on larger, multidomain proteins, which comprise the majority of proteins, is less advanced. Specifically, large proteins often fold via long-lived partially folded intermediates, whose structures, potentially toxic oligomerization, and interactions with cellular chaperones remain poorly understood. Molecular dynamics based folding simulations that rely on knowledge of the native structure can provide critical, detailed information on folding free energy landscapes, intermediates, and pathways. Further, increases in computational power and methodological advances have made folding simulations of large proteins practical and valuable. Here, using serpins that inhibit proteases as an example, we review native-centric methods for simulating the folding of large proteins. These synergistic approaches range from Gō and related structurebased models that can predict the effects of the native structure on folding to all-atom-based methods that include side-chain chemistry and can predict how disease-associated mutations may impact folding. The application of these computational approaches to serpins and other large proteins highlights the successes and limitations of current computational methods and underscores how computational results can be used to inform experiments. These powerful simulation approaches in combination with experiments can provide unique insights into how large proteins fold and misfold, expanding our ability to predict and manipulate protein folding.

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Chaperone-client interactions: Non-specificity engenders multifunctionality

Cited by 66 publications

References 101 publications

Mechanistic insights into NAD synthase NMNAT chaperoning phosphorylated Tau from pathological aggregation

Mechanistic insights into NAD synthase NMNAT chaperoning phosphorylated Tau from pathological aggregation

Heat shock protein 104 (HSP104) chaperones soluble Tau via a mechanism distinct from its disaggregase activity

Successes and challenges in simulating the folding of large proteins

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