RNA molecules with conserved catalytic cores but variable peripheries fold along unique energetically optimized pathways

Somdeb Mitra, Alain Laederach, Barbara L. Golden, Russ B. Altman, Michael D. Brenowitz

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Functional and kinetic constraints must be efficiently balanced during the folding process of all biopolymers. To understand how homologous RNA molecules with different global architectures fold into a common core structure we determined, under identical conditions, the folding mechanisms of three phylogenetically divergent group I intron ribozymes. These ribozymes share a conserved functional core defined by topologically equivalent tertiary motifs but differ in their primary sequence, size, and structural complexity. Time-resolved hydroxyl radical probing of the backbone solvent accessible surface and catalytic activity measurements integrated with structural-kinetic modeling reveal that each ribozyme adopts a unique strategy to attain the conserved functional fold. The folding rates are not dictated by the size or the overall structural complexity, but rather by the strength of the constituent tertiary motifs which, in turn, govern the structure, stability, and lifetime of the folding intermediates. A fundamental general principle of RNA folding emerges from this study: The dominant folding flux always proceeds through an optimally structured kinetic intermediate that has sufficient stability to act as a nucleating scaffold while retaining enough conformational freedom to avoid kinetic trapping. Our results also suggest a potential role of naturally selected peripheral A-minor interactions in balancing RNA structural stability with folding efficiency.

Original languageEnglish (US)
Pages (from-to)1589-1603
Number of pages15
JournalRNA
Volume17
Issue number8
DOIs
StatePublished - Aug 2011

Fingerprint

Catalytic Domain
RNA
Catalytic RNA
RNA Folding
Biopolymers
RNA Stability
Hydroxyl Radical
Introns

Keywords

  • Group I introns
  • Kinetic intermediates
  • Ribozymes
  • RNA folding
  • Structural homology

ASJC Scopus subject areas

  • Molecular Biology

Cite this

RNA molecules with conserved catalytic cores but variable peripheries fold along unique energetically optimized pathways. / Mitra, Somdeb; Laederach, Alain; Golden, Barbara L.; Altman, Russ B.; Brenowitz, Michael D.

In: RNA, Vol. 17, No. 8, 08.2011, p. 1589-1603.

Research output: Contribution to journalArticle

Mitra, Somdeb ; Laederach, Alain ; Golden, Barbara L. ; Altman, Russ B. ; Brenowitz, Michael D. / RNA molecules with conserved catalytic cores but variable peripheries fold along unique energetically optimized pathways. In: RNA. 2011 ; Vol. 17, No. 8. pp. 1589-1603.
@article{be9786431ad0464aa69051f1eb64ed26,
title = "RNA molecules with conserved catalytic cores but variable peripheries fold along unique energetically optimized pathways",
abstract = "Functional and kinetic constraints must be efficiently balanced during the folding process of all biopolymers. To understand how homologous RNA molecules with different global architectures fold into a common core structure we determined, under identical conditions, the folding mechanisms of three phylogenetically divergent group I intron ribozymes. These ribozymes share a conserved functional core defined by topologically equivalent tertiary motifs but differ in their primary sequence, size, and structural complexity. Time-resolved hydroxyl radical probing of the backbone solvent accessible surface and catalytic activity measurements integrated with structural-kinetic modeling reveal that each ribozyme adopts a unique strategy to attain the conserved functional fold. The folding rates are not dictated by the size or the overall structural complexity, but rather by the strength of the constituent tertiary motifs which, in turn, govern the structure, stability, and lifetime of the folding intermediates. A fundamental general principle of RNA folding emerges from this study: The dominant folding flux always proceeds through an optimally structured kinetic intermediate that has sufficient stability to act as a nucleating scaffold while retaining enough conformational freedom to avoid kinetic trapping. Our results also suggest a potential role of naturally selected peripheral A-minor interactions in balancing RNA structural stability with folding efficiency.",
keywords = "Group I introns, Kinetic intermediates, Ribozymes, RNA folding, Structural homology",
author = "Somdeb Mitra and Alain Laederach and Golden, {Barbara L.} and Altman, {Russ B.} and Brenowitz, {Michael D.}",
year = "2011",
month = "8",
doi = "10.1261/rna.2694811",
language = "English (US)",
volume = "17",
pages = "1589--1603",
journal = "RNA",
issn = "1355-8382",
publisher = "Cold Spring Harbor Laboratory Press",
number = "8",

}

TY - JOUR

T1 - RNA molecules with conserved catalytic cores but variable peripheries fold along unique energetically optimized pathways

AU - Mitra, Somdeb

AU - Laederach, Alain

AU - Golden, Barbara L.

AU - Altman, Russ B.

AU - Brenowitz, Michael D.

PY - 2011/8

Y1 - 2011/8

N2 - Functional and kinetic constraints must be efficiently balanced during the folding process of all biopolymers. To understand how homologous RNA molecules with different global architectures fold into a common core structure we determined, under identical conditions, the folding mechanisms of three phylogenetically divergent group I intron ribozymes. These ribozymes share a conserved functional core defined by topologically equivalent tertiary motifs but differ in their primary sequence, size, and structural complexity. Time-resolved hydroxyl radical probing of the backbone solvent accessible surface and catalytic activity measurements integrated with structural-kinetic modeling reveal that each ribozyme adopts a unique strategy to attain the conserved functional fold. The folding rates are not dictated by the size or the overall structural complexity, but rather by the strength of the constituent tertiary motifs which, in turn, govern the structure, stability, and lifetime of the folding intermediates. A fundamental general principle of RNA folding emerges from this study: The dominant folding flux always proceeds through an optimally structured kinetic intermediate that has sufficient stability to act as a nucleating scaffold while retaining enough conformational freedom to avoid kinetic trapping. Our results also suggest a potential role of naturally selected peripheral A-minor interactions in balancing RNA structural stability with folding efficiency.

AB - Functional and kinetic constraints must be efficiently balanced during the folding process of all biopolymers. To understand how homologous RNA molecules with different global architectures fold into a common core structure we determined, under identical conditions, the folding mechanisms of three phylogenetically divergent group I intron ribozymes. These ribozymes share a conserved functional core defined by topologically equivalent tertiary motifs but differ in their primary sequence, size, and structural complexity. Time-resolved hydroxyl radical probing of the backbone solvent accessible surface and catalytic activity measurements integrated with structural-kinetic modeling reveal that each ribozyme adopts a unique strategy to attain the conserved functional fold. The folding rates are not dictated by the size or the overall structural complexity, but rather by the strength of the constituent tertiary motifs which, in turn, govern the structure, stability, and lifetime of the folding intermediates. A fundamental general principle of RNA folding emerges from this study: The dominant folding flux always proceeds through an optimally structured kinetic intermediate that has sufficient stability to act as a nucleating scaffold while retaining enough conformational freedom to avoid kinetic trapping. Our results also suggest a potential role of naturally selected peripheral A-minor interactions in balancing RNA structural stability with folding efficiency.

KW - Group I introns

KW - Kinetic intermediates

KW - Ribozymes

KW - RNA folding

KW - Structural homology

UR - http://www.scopus.com/inward/record.url?scp=79960466968&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79960466968&partnerID=8YFLogxK

U2 - 10.1261/rna.2694811

DO - 10.1261/rna.2694811

M3 - Article

C2 - 21712400

AN - SCOPUS:79960466968

VL - 17

SP - 1589

EP - 1603

JO - RNA

JF - RNA

SN - 1355-8382

IS - 8

ER -