Structure and Molecular Dynamics Simulation of Archaeal Prefoldin: The Molecular Mechanism for Binding and Recognition of Nonnative Substrate Proteins

Ohtaki, Akashi; Kida, Hiroshi; Miyata, Yusuke; Ide, Naoki; Yonezawa, Akinori; Arakawa, T.; Iizuka, Ryo; Noguchi, Keiichi; Kita, Akiko; Odaka, Masafumi; Miki, Kunio; Yohda, Masafumi

doi:10.1016/j.jmb.2007.12.010

Cited by 54 publications

(57 citation statements)

References 28 publications

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“…The rmsf values of the b-sheet barrel backbone were < 2 A, showing a low level of flexibility and stable structure. Thus, this bsheet assembly helps maintain this unique structure and the width of the central cavity, which has also been observed for a 2 /b 4 PFD complexes [7,15].…”

Section: Dynamic Structure Of Cpfd Filamentssupporting

confidence: 55%

“…The flexibility of these coiledcoils' 'tentacles' is critical for enabling the central cavity of the a 2 /b 4 PFD assembly to widen and accommodate various unfolded proteins [7,15]. MD simulations were used to examine the flexibility of the coiled-coils in cPFD filaments at varying temperatures.…”

Section: Dynamic Structure Of Cpfd Filamentsmentioning

confidence: 99%

“…In addition, the short hydrogen-bonded turns (composed of residues 59-62, 70-74 and 79-82) that link the b sheets together exhibited a greater degree of flexibility at 353 K. It has previously been suggested that the loops that link the a-helical and b-sheet regions of a 2 /b 4 PFD complexes function as a 'hinge' to enable flexible motions of the coiled-coils in all subunits [7]. However, in the cPFD simulation, the regions that connect a-helical and b-sheet regions were relatively rigid.…”

Section: Dynamic Structure Of Cpfd Filamentsmentioning

confidence: 99%

“…The PFDs are typically hetero-hexameric complexes found in both Archaea and eukaryotes, which have diverged in subunit composition, from two a and four b subunits in Archaea to six different subunits in eukaryotes. However, the quaternary structures of archaeal and eukaryotic PFD are essentially identical, with a jellyfish-like assembly of six coiled-coils protruding from a double b-sheet barrel backbone that functions as the oligomerization region [6,7]. Within eukaryotic cells, PFD participates in the maturation of mainly cytoskeletal proteins that include actin and tubulin in conjunction with other chaperone families [2,4,6].…”

Section: Introductionmentioning

confidence: 99%

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Oligomeric assembly is required for chaperone activity of the filamentous γ‐prefoldin

Glover

Clark

2015

The FEBS Journal

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Prefoldins (PFDs) are molecular chaperones with a distinctive jellyfishshape that have a general role in de novo protein folding in Archaea and in the biogenesis of cytoskeleton proteins in eukaryotes. In general, PFDs are hetero-hexameric protein assemblies consisting of two a and four b subunits. However, a PFD variant called gamma-prefoldin (cPFD), isolated from the hyperthermophilic archaeon Methanocaldococcus jannaschii, exhibits a unique filamentous structure that is composed of hundreds of monomeric subunits. In this study, we investigated the relationship between the morphology of the cPFD filament and its ability to prevent protein aggregation. A chaperone assay demonstrated that cPFD must be in a filamentous assembly for functional activity and the distal regions of the coiled-coils are required for binding of non-native proteins. Molecular dynamic simulations were used to model the interactions between in silico thermally denatured protein substrates and the coiled-coils of a cPFD filament. During molecular dynamic simulations at 300 and 353 K, each coiled-coil was highly flexible, enabling it to widen the central cavity of the filament to potentially capture various non-native proteins. Docking molecular dynamic simulations of cPFD filaments with unfolded citrate synthase or insulin showed a size-dependence between the substrate and the number of interacting coiled-coils. To confirm this observation, we generated filaments containing specific numbers of subunits, and showed that between six and eight cPFD subunits are required for chaperone activity to prevent citrate synthase from thermal aggregation. These results provide insights into structure-function relationships of oligomeric chaperones and illuminate the potential role of cPFD in its native environment.

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Section: Dynamic Structure Of Cpfd Filamentssupporting

confidence: 55%

Section: Dynamic Structure Of Cpfd Filamentsmentioning

confidence: 99%

Section: Dynamic Structure Of Cpfd Filamentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oligomeric assembly is required for chaperone activity of the filamentous γ‐prefoldin

Glover

Clark

2015

The FEBS Journal

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“…Ohtaki et al (40) predict from their electron microscopy and biochemical studies that the ␤-subunits (PFDN1, -2, -4, and -6) are crucial for nonnative protein binding (40). They also suggest that the ␣ subunits (PFDN3 and -5) may be involved in substrate specificity and stabilizing the complex of prefoldin/substrate by changing their conformation and position according to substrate size and mode of binding (40).…”

Section: Discussionmentioning

confidence: 99%

Prefoldin 5 Is Required for Normal Sensory and Neuronal Development in a Murine Model

Lee

Smith

Jordan

et al. 2011

Journal of Biological Chemistry

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Molecular chaperones and co-chaperones are crucial for cellular development and maintenance as they assist in protein folding and stabilization of unfolded or misfolded proteins. Prefoldin (PFDN), a ubiquitously expressed heterohexameric co-chaperone, is necessary for proper folding of nascent proteins, in particular, tubulin and actin. Here we show that a genetic disruption in the murine Pfdn5 gene, a subunit of prefoldin, causes a syndrome characterized by photoreceptor degeneration, central nervous system abnormalities, and male infertility. Our data indicate that a missense mutation in Pfdn5, may cause these phenotypes through a reduction in formation of microtubules and microfilaments, which are necessary for the development of cilia and cytoskeletal structures, respectively. The diversity of phenotypes demonstrated by models carrying mutations in different PFDN subunits suggests that each PFDN subunit must confer a distinct substrate specificity to the prefoldin holocomplex.

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Prefoldin subunit 6 of Plasmodium falciparum binds merozoite surface protein‐1

et al. 2022

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Malaria is a human disease caused by eukaryotic protozoan parasites of the Plasmodium genus. Plasmodium falciparum (Pf) causes the most lethal form of human malaria and is responsible for widespread mortality worldwide. Prefoldin is a hetero-hexameric molecular complex that binds and delivers unfolded proteins to chaperonin for correct folding. The prefoldin PFD6 is predicted to interact with merozoite surface protein-1 (MSP-1), a protein well known to play a pivotal role in erythrocyte binding and invasion by Plasmodium merozoites. We previously found that the Plasmodium falciparum (Pf) genome contains six prefoldin genes and a prefoldin-like gene whose molecular functions are unidentified. Here, we analysed the expression of PfPFD-6 during the asexual blood stages of the parasite and investigated its interacting partners. PfPFD-6 was found to be significantly expressed at the trophozoite and schizont stages. Pull down assays suggest PfPFD-6 interacts with MSP-1. In silico analysis suggested critical residues involved in the PfPFD-6-MSP-1 interaction. Our data suggest PfPFD-6 may play a role in stabilizing or trafficking MSP-1.

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Structure and Molecular Dynamics Simulation of Archaeal Prefoldin: The Molecular Mechanism for Binding and Recognition of Nonnative Substrate Proteins

Cited by 54 publications

References 28 publications

Oligomeric assembly is required for chaperone activity of the filamentous γ‐prefoldin

Oligomeric assembly is required for chaperone activity of the filamentous γ‐prefoldin

Prefoldin 5 Is Required for Normal Sensory and Neuronal Development in a Murine Model

Prefoldin subunit 6 of Plasmodium falciparum binds merozoite surface protein‐1

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