Abstract:
BACKGROUND:A basic tenet of protein science is that all information about the spatial structure of proteins is present in their sequences. Nonetheless, many proteins fail to attain native structure upon experimental denaturation and refolding in vitro, raising the question of the specific role of cellular machinery in protein folding in vivo. Recently, we hypothesized that energy-dependent twisting of the protein backbone is an unappreciated essential factor guiding the protein folding process in vivo. Torque force may be applied by the ribosome co-translationally, and when accompanied by simultaneous restriction of the rotational mobility of the distal part of the growing chain, the resulting tension in the protein backbone would facilitate the formation of local secondary structure and direct the folding process. RESULTS:Our model of the early stages of protein folding in vivo postulates that the free motion of both terminal regions of the protein during its synthesis and maturation is restricted. The long-known but unexplained phenomenon of statistical overrepresentation of protein termini on the surfaces of the protein structures may be an indication of the backbone twist-based folding mechanism; sustained maintenance of a twist requires that both ends of the protein chain are anchored in space, and if the ends are released only after the majority of folding is complete, they are much more likely to remain on the surface of the molecule. We identified the molecular components that are likely to play a role in the twisting of the nascent protein chain and in the anchoring of its N-terminus. The twist may be induced at the C-terminus of the nascent polypeptide by the peptidyltransferase center of the ribosome. Several ribosome-associated proteins, including the trigger factor in bacteria and the nascent polypeptide-associated complex in archaea and eukaryotes, may restrict the rotational mobility of the N-proximal regions of the peptides. CONCLUSIONS:Many experimental observations are consistent with the hypothesis of co-translational twisting of the protein backbone. Several molecular players in this hypothetical mechanism of protein folding can be suggested. In addition, the new view of protein folding in vivo opens the possibility of novel potential drug targets to combat human protein folding diseases. REVIEWERS:This article was reviewed by Lakshminarayan Iyer and István Simon.
journal_name
Biol Directjournal_title
Biology directauthors
Sorokina I,Mushegian Adoi
10.1186/s13062-017-0186-1subject
Has Abstractpub_date
2017-05-31 00:00:00pages
14issue
1issn
1745-6150pii
10.1186/s13062-017-0186-1journal_volume
12pub_type
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