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Functional dynamics of the folded ankyrin repeats of i kappa b alpha revealed by nuclear magnetic resonance

Academic Article
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Overview

authors

  • Cervantes, C. F.
  • Markwick, P. R. L.
  • Sue, S. C.
  • McCammon, J. A.
  • Dyson, Jane
  • Komives, E. A.

publication date

  • August 2009

journal

  • Biochemistry  Journal

abstract

  • Inhibition of nuclear factor kappaB (NF-kappaB) is mainly accomplished by IkappaB alpha, which consists of a signal response sequence at the N-terminus, a six-ankyrin repeat domain (ARD) that binds NF-kappaB, and a C-terminal PEST sequence. Previous studies with the ARD revealed that the fifth and sixth repeats are only partially folded in the absence of NF-kappaB. Here we report NMR studies of a truncated version of IkappaB alpha, containing only the first four ankyrin repeats, IkappaB alpha(67-206). This four-repeat segment is well-structured in the free state, enabling full resonance assignments to be made. H-D exchange, backbone dynamics, and residual dipolar coupling (RDC) experiments reveal regions of flexibility. In addition, regions consistent with the presence of micro- to millisecond motions occur periodically throughout the repeat structure. Comparison of the RDCs with the crystal structure gave only moderate agreement, but an ensemble of structures generated by accelerated molecular dynamics gave much better agreement with the measured RDCs. The regions showing flexibility correspond to those implicated in entropic compensation for the loss of flexibility in ankyrin repeats 5 and 6 upon binding to NF-kappaB. The regions showing micro- to millisecond motions in the free protein are the ends of the beta-hairpins that directly interact with NF-kappaB in the complex.

subject areas

  • Amino Acid Sequence
  • Animals
  • Ankyrin Repeat
  • Deuterium Exchange Measurement
  • Humans
  • I-kappa B Kinase
  • Mice
  • Molecular Sequence Data
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptide Fragments
  • Protein Binding
  • Protein Folding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Thermodynamics
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Identity

PubMed Central ID

  • PMC2728578

International Standard Serial Number (ISSN)

  • 0006-2960

Digital Object Identifier (DOI)

  • 10.1021/bi900712r

PubMed ID

  • 19591507
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Additional Document Info

start page

  • 8023

end page

  • 8031

volume

  • 48

issue

  • 33

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