The energy landscape of modular repeat proteins: topology determines folding mechanism in the ankyrin family

J Mol Biol. 2005 Dec 2;354(3):679-92. doi: 10.1016/j.jmb.2005.09.078. Epub 2005 Oct 13.

Abstract

Proteins consisting of repeating amino acid motifs are abundant in all kingdoms of life, especially in higher eukaryotes. Repeat-containing proteins self-organize into elongated non-globular structures. Do the same general underlying principles that dictate the folding of globular domains apply also to these extended topologies? Using a simplified structure-based model capturing a perfectly funneled energy landscape, we surveyed the predicted mechanism of folding for ankyrin repeat containing proteins. The ankyrin family is one of the most extensively studied classes of non-globular folds. The model based only on native contacts reproduces most of the experimental observations on the folding of these proteins, including a folding mechanism that is reminiscent of a nucleation propagation growth. The confluence of simulation and experimental results suggests that the folding of non-globular proteins is accurately described by a funneled energy landscape, in which topology plays a determinant role in the folding mechanism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Amino Acid Sequence
  • Ankyrins / chemistry*
  • Ankyrins / classification
  • Ankyrins / metabolism*
  • Computer Simulation
  • I-kappa B Kinase / chemistry
  • I-kappa B Kinase / metabolism
  • Kinetics
  • Molecular Sequence Data
  • Protein Folding*
  • Receptors, Notch / chemistry
  • Receptors, Notch / metabolism
  • Thermodynamics

Substances

  • Ankyrins
  • Receptors, Notch
  • I-kappa B Kinase