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

Prefoldin (PFD) is a heterohexameric molecular chaperone complex in the eukaryotic cytosol and archaea with a jellyfish-like structure containing six long coiled-coil tentacles. PFDs capture protein folding intermediates or unfolded polypeptides and transfer them to group II chaperonins for facilita...

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Published in:Journal of molecular biology 2008-02, Vol.376 (4), p.1130-1141
Main Authors: Ohtaki, Akashi, Kida, Hiroshi, Miyata, Yusuke, Ide, Naoki, Yonezawa, Akihiro, Arakawa, Takatoshi, Iizuka, Ryo, Noguchi, Keiichi, Kita, Akiko, Odaka, Masafumi, Miki, Kunio, Yohda, Masafumi
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Archaea
chaperone
Citrate (si)-Synthase - chemistry
Computer Simulation
Crystallography, X-Ray
Green Fluorescent Proteins - chemistry
group II chaperonin
Hydrophobic and Hydrophilic Interactions
Insulin
Models, Molecular
Molecular Chaperones - chemistry
molecular dynamics
Mutant Proteins - chemistry
Mutation - genetics
prefoldin
Protein Binding
Protein Folding
Protein Structure, Secondary
Protein Subunits - chemistry
Pyrococcus horikoshii
Pyrococcus horikoshii - chemistry
Temperature
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Summary:Prefoldin (PFD) is a heterohexameric molecular chaperone complex in the eukaryotic cytosol and archaea with a jellyfish-like structure containing six long coiled-coil tentacles. PFDs capture protein folding intermediates or unfolded polypeptides and transfer them to group II chaperonins for facilitated folding. Although detailed studies on the mechanisms for interaction with unfolded proteins or cooperation with chaperonins of archaeal PFD have been performed, it is still unclear how PFD captures the unfolded protein. In this study, we determined the X-ray structure of Pyrococcus horikoshii OT3 PFD (PhPFD) at 3.0 Å resolution and examined the molecular mechanism for binding and recognition of nonnative substrate proteins by molecular dynamics (MD) simulation and mutation analyses. PhPFD has a jellyfish-like structure with six long coiled-coil tentacles and a large central cavity. Each subunit has a hydrophobic groove at the distal region where an unfolded substrate protein is bound. During MD simulation at 330 K, each coiled coil was highly flexible, enabling it to widen its central cavity and capture various nonnative proteins. Docking MD simulation of PhPFD with unfolded insulin showed that the β subunit is essentially involved in substrate binding and that the α subunit modulates the shape and width of the central cavity. Analyses of mutant PhPFDs with amino acid replacement of the hydrophobic residues of the β subunit in the hydrophobic groove have shown that βIle107 has a critical role in forming the hydrophobic groove.
ISSN:0022-2836
1089-8638
DOI:10.1016/j.jmb.2007.12.010