Prefoldin, a jellyfish-like molecular chaperone: functional cooperation with a group II chaperonin and beyond

Abstract

Prefoldin is a hexameric molecular chaperone found in the cytosol of archaea and eukaryotes. Its hexameric complex is built from two related classes of subunits and has the appearance of a jellyfish: its body consists of a double beta-barrel assembly with six long tentacle-like coiled coils protruding from it. Using the tentacles, prefoldin captures an unfolded protein substrate and transfers it to a group II chaperonin. The prefoldin-group II chaperonin system is thought to be important for the folding of newly synthesized proteins and for their maintenance, or proteostasis, in the cytosol. Based on structural information of archaeal prefoldins, the mechanisms of substrate recognition and prefoldin-chaperonin cooperation have been investigated. In contrast, the role and mechanism of eukaryotic PFDs remain unknown. Recent studies have shown that prefoldin plays an important role in proteostasis and is involved in various diseases. In this paper, we review a series of studies on the molecular mechanisms of archaeal prefoldins and introduce recent findings about eukaryotic prefoldin.

Keywords: Chaperonin; Molecular chaperone; Prefoldin.

Fig. 1

Crystal structure of Pyrococcus prefoldin. Overall structure of the α₂β₄ hexameric complex of Pyrococcus PFD showing side and bottom views. α subunits and β subunits are shown in red (α subunit), green, and blue (β subunit). Reproduced with permission from Ohtaki et al.

Fig. 2

Amino acid residues responsible for the interactions of Pyrococcus PFD with substrate and chaperonin. a The overall structure of α and β subunits. The hydrophobic residues (αLeu11, αLeu14, αVal131, αVal13, βLeu8, βLeu12, βLeu15, βLeu103, and βIle107) in the distal region of each subunit are in CPK representation. b The structure of the hydrophobic grooves of the α and β subunits at the distal region of the coiled coil. The hydrophobic residues are shown as ball-and-stick models. Reproduced with permission from Ohtaki et al.

Fig. 3

Two important amino acid residues for the interaction of the helical protrusion regions of the apical domain of chaperonin with Pyrococcus PFD. a Amino acid sequence alignment of the helical protrusion regions (246–276 aa) of Pyrococcus CPN, Thermococcus CPNβ, and CPNα. The two amino acid residues at the 250th and 256th positions, which have opposite electric charges between CPNα and Pyrococcus PFD and CPNβ, are highlighted. Amino acid residues conserved in CPNα are marked by asterisks. b Structure of the CPNα subunit. The apical, intermediate, and equatorial domains are colored blue, yellow, and red, respectively. Lys250 and Lys256 are shown by the CPK model. The coordinates are from the Protein Data Bank code 1Q3S. c Effects of mutations in Lys250 and Lys256 on the affinity for Pyrococcus PFD. Pyrococcus PFD was immobilized on a Biacore biosensor chip. Sensorgrams of CPNα, CPNαK256E, CPNαK250E, CPNαK250E/K256E, and CPNβ are shown for comparison. The largest SPR signal value of CPNαK250E/K256E at 300 s was taken as 100%. Reproduced with permission from Zako et al.

Fig. 4

Schematic images for the complex of PFD and group II chaperonin. a Total view of the PFD-CPN complex. Only half a ring of CPN is shown. b The interaction sites between the CPN monomer and the prefoldin β subunit is shown