Accurate folding is essential for the proper function of proteins. Prefoldin is one of the chaperoning factors that contribute to protein folding in archaea and eukaryotes. Although it still has maintained its heterohexameric jellyfish‐like structure, it has undergone a progressive diversification throughout evolution, which has ended up with the appearance of the prefoldin‐like complex. This evolutionary change parallels an increasing specificity for substrate recognition, from general binding to unfolded polypeptides in archaea to the highly specific recognition of certain substrates in eukaryotes. Prefoldin action on unfolded polypeptides contributes to its solubilisation in vitro, but acts mainly in vivo as a cochaperone, by transferring nascent polypeptides to class‐II chaperonins. This role of prefoldin is particularly relevant in the assembly of actin filaments and microtubules. In addition to this function, prefoldins also play important roles in the assembly of other multimeric complexes, protein quality control, transcription factors regulation and chromatin dynamics.

Key Concepts

  • Prefoldins are heterohexameric jellyfish‐like complexes present in archaea and eukaryotes.
  • Prefoldin acts as a cochaperone and facilitates the supply of unfolded or partially folded substrates to class II chaperonins.
  • Archaeal prefoldin recognises a wide range of unfolded substrates, whereas eukaryotic prefoldin is highly specific.
  • The best‐known role of eukaryotic prefoldin is the cotranslational transfer of nascent actin and tubulin monomers to cytoplasmic class‐II chaperonins for proper folding.
  • Canonical prefoldin also plays functional roles related to gene expression and chromatin dynamics in the nucleus.
  • The prefoldin‐like complex exists only in eukaryotes and is involved in the assembly of multimeric protein complexes, such as nuclear RNA polymerases and phosphatidylinositol‐3‐kinase‐related protein kinases like mTOR.

Keywords: prefoldin; protein folding; cochaperone; cytoskeleton; prefoldin‐like; chaperonin

Figure 1. Structure of prefoldin subunits and complex. (a) The number of β‐hairpins that the two types of prefoldin subunits contain differs. In the α subunits, two β‐hairpins are located between two α‐helical coiled coils, whereas there is only one β‐hairpin in the β subunits. (b) Atomic structure of the archaeal prefoldin of M. thermoautotrophicum, as represented in Martin‐Benito et al. (). (c) Order and physical interactions of the six canonical eukaryotic subunits illustrated with a reconstruction of human prefoldin (Martin‐Benito et al., ). (b,c) Reproduced with permission from Martin‐Benito et al. (2002) © John Wiley and Sons.
Figure 2. Diversification of prefoldin throughout evolution. Some archaea, like some Pyrococcus strains, contain only one α subunit and one β subunit. In Methanococcus, a third type of prefoldin appears, γ‐prefoldin, although it does not form part of canonical prefoldin. This γ‐type is the origin of the eubacterial prefoldin present in Aquifex aeolicus, likely acquired by horizontal transfer. Diversification of canonical prefoldin already started in the archaeal kingdom as some Thermococcus strains express two α and two β subunits. All eukaryotes contain two different α and four different β subunits. In addition, all eukaryotes show the noncanonical subunit URI, an α‐type subunit that contributes to the prefoldin‐like complex. A second step in the evolution of eukaryotes represents the appearance of a second α‐like noncanonical subunit, UXT. Finally, the prefoldin‐like complex of higher metazoan, like Drosophila and humans, contains the β‐like subunit PDRG1.
Figure 3. Substrate binding by prefoldin. (a) Hypothetical model of the interaction between archaeal prefoldin from Pyrococcus horikoshii and conalbumin based on three‐dimensional reconstruction after electron microscopy observations. Archaeal prefoldin utilises the tentacle tips to interact with and to stabilise its unfolded substrates. (b) Hypothetical model of the interaction between human prefoldin and actin based on three‐dimensional reconstruction after electron microscopy observations. Eukaryotic prefoldin encapsulates its substrate inside the cavity. Images kindly supplied by José María Valpuesta.
Figure 4. In addition to contributing to cytoskeleton assembly, prefoldins participate in several other processes in eukaryotic cells in both the cytoplasm and the nucleus. See the text for details.


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Further Reading

Hartl FU and Hayer‐Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295: 1852–1858.

Lundin VF, Leroux MR and Stirling PC (2010) Quality control of cytoskeletal proteins and human disease. Trends in Biochemical Sciences 35: 288–297.

Millan‐Zambrano G and Chavez S (2014) Nuclear functions of prefoldin. Open Biology 4: pii 140085.

Ohtaki A, Noguchi K and Yohda M (2010) Structure and function of archaeal prefoldin, a co‐chaperone of group II chaperonin. Frontiers in Bioscience 15: 708–717.

Stirling PC, Bakhoum SF, Feigl AB and Leroux MR (2006) Convergent evolution of clamp‐like binding sites in diverse chaperones. Nature Structural & Molecular Biology 13: 865–870.

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Chávez, Sebastián, and Puerto‐Camacho, Pilar(Apr 2016) Prefoldins. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026334]