Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 13, 1-20

RNA Misfolding and the Action of Chaperones

Affiliations
Review

RNA Misfolding and the Action of Chaperones

Rick Russell. Front Biosci.

Abstract

RNA folds to a myriad of three-dimensional structures and performs an equally diverse set of functions. The ability of RNA to fold and function in vivo is all the more remarkable because, in vitro, RNA has been shown to have a strong propensity to adopt misfolded, non-functional conformations. A principal factor underlying the dominance of RNA misfolding is that local RNA structure can be quite stable even in the absence of enforcing global tertiary structure. This property allows non-native structure to persist, and it also allows native structure to form and stabilize non-native contacts or non-native topology. In recent years it has become clear that one of the central reasons for the apparent disconnect between the capabilities of RNA in vivo and its in vitro folding properties is the presence of RNA chaperones, which facilitate conformational transitions of RNA and therefore mitigate the deleterious effects of RNA misfolding. Over the past two decades, it has been demonstrated that several classes of non-specific RNA binding proteins possess profound RNA chaperone activity in vitro and when overexpressed in vivo, and at least some of these proteins appear to function as chaperones in vivo. More recently, it has been shown that certain DExD/H-box proteins function as general chaperones to facilitate folding of group I and group II introns. These proteins are RNA-dependent ATPases and have RNA helicase activity, and are proposed to function by using energy from ATP binding and hydrolysis to disrupt RNA structure and/or to displace proteins from RNA-protein complexes. This review outlines experimental studies that have led to our current understanding of the range of misfolded RNA structures, the physical origins of RNA misfolding, and the functions and mechanisms of putative RNA chaperone proteins.

Figures

Figure 1
Figure 1
RNA pseudoknots. A, A pseudoknot is formed when loop nucleotides form base pairs with a region outside the loop. Shown is a simple pseudoknot structure from beet western yellow virus (207). B, A double-pseudoknotted RNA structure, the hepatitis delta virus (HDV) ribozyme. Pseudoknots are formed between nucleotides within a hairpin loop and nucleotides outside the hairpin. In the HDV ribozyme, helices P1.1 and P2 are pseudoknots. Outlined nucleotides are non-natural and were introduced to aid in crystallization (reproduced from ref. by permission from Macmillan Publishers Ltd: Nature, copyright 1998).
Figure 2
Figure 2
A-minor tertiary interactions. A, Crystal structure of the P4-P6 domain of the Tetrahymena group I ribozyme, which includes a tetraloop-receptor interaction (boxed). The GAAA tetraloop sequence (gold) forms tertiary contacts with its receptor sequence (green). The domain also includes an internal loop (orange) that forms A-minor interactions with the adjacent helix. A third helix in the domain (black) forms a tertiary contact composed of base-pairing interactions (the partner was not part of the molecule crystallized and not shown). This panel is reproduced with permission from ref. . Copyright 1996, AAAS. B, A-minor tertiary interactions. Adenosine nucleotides form contacts in the minor groove of a helix, most commonly with G-C pairs as shown. The specific contacts for type I and type II interactions are shown. This panel is reprinted from ref. (Copyright 2001 National Academy of Sciences, U.S.A.), and the contacts shown are within the 23S rRNA.
Figure 3
Figure 3
Model for misfolding of tRNA. A, Native secondary structure of E. coli tRNAGlu. B, Proposed misfolded secondary structure. Non-native base pairs are formed between nucleotides in the D loop and the TψC loops, disrupting the corresponding stems. The model is based on data and interpretations in ref. .
Figure 4
Figure 4
Misfolding of the Tetrahymena group I ribozyme. A, Secondary structure of the ribozyme. Long-range tertiary contacts are shown with thick arrows. The P3/altP3 region is highlighted in gray. B, Exchange of the native P3 and non-native alt P3 secondary structures. The structure at the left shows the native P3, as also shown in panel A. The structure at the right shows formation of the non-native alt P3 structure and disruption of P3. C, A topological difference between misfolded and native structures. The top panel shows the native topology within the core of the ribozyme and the bottom panel shows one of several possible incorrect topologies that may be present in the long-lived misfolded structure. D, A model for how a non-native secondary structure can bias an RNA to misfold by giving an incorrect topology, without the non-native secondary structure remaining present in the most stable misfolded form. Formation of the local and non-native structure alt P3 (purple circle) biases the RNA to adopt an incorrect topology early in folding, and this incorrect topology is maintained throughout folding to the misfolded structure even though the secondary structure is exchanged for the native P3 at a later point in folding. Reprinted from ref. with permission from Elsevier.
Figure 5
Figure 5
Nucleic acid binding by the cold-shock protein CspB. Two molecular of an oligonucletide of six thymidine nucleotides (dT6, shown in red) were bound to CspB in the crystal, as shown. The protein is shown as a semi-transparent surface, and carbons of residues on the protein that contact the oligonucleotide are colored green. Reprinted from ref. with permission from Elsevier.
Figure 6
Figure 6
Model for chaperone activity of CYT-19. CYT-19 binds to structured RNA via a site on the protein that is distinct from the site responsible for unwinding helices or performing other structure-disruption activities (labeled RBD). This site remains bound at its attachment point while the ATP-dependent structure-disruption occurs. The figure shows unwinding of the helix of the Tetrahymena ribozyme formed between the ribozyme and its oligonucleotide substrate (colored green and red, respectively). The secondary elements of the ribozyme are depicted as black and blue cylinders for core and peripheral elements, respectively. Reprinted from ref. (Copyright 2006 National Academy of Sciences, U.S.A.).

Similar articles

See all similar articles

Cited by 65 PubMed Central articles

See all "Cited by" articles

Publication types

Feedback