Force-Induced Unfolding of Leucine-Rich Repeats of Glycoprotein Ibα Strengthens Ligand Interaction

Biophys J. 2015 Nov 3;109(9):1781-4. doi: 10.1016/j.bpj.2015.08.050.

Abstract

Leucine-rich repeat (LRR) is a versatile motif widely present in adhesive proteins and signal-transducing receptors. The concave structure formed by a group of LRRs is thought to facilitate binding to globular protein domains with increased affinities. However, little is known about the conformational dynamics of LRRs in such a structure, e.g., whether and how force induces conformational changes in LRRs to regulate protein binding and signal transduction. Here we investigated the platelet glycoprotein Ibα (GPIbα), a demonstrated mechanoreceptor with known crystal structures for the N-terminal domain (GPIbαN), as a model for LRR-containing proteins using a combined method of steered molecular dynamics simulations and single-molecule force spectroscopy with a biomembrane force probe. We found that force-induced unfolding of GPIbαN starts with LRR2-4 and propagates to other LRRs. Importantly, force-dependent lifetimes of individual VWF-A1 bonds with GPIbα are prolonged after LRR unfolding. Enhancement of protein-protein interactions by force-induced LRR unfolding may be a phenomenon of interest in biology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Leucine / chemistry
  • Molecular Dynamics Simulation
  • Platelet Glycoprotein GPIb-IX Complex / metabolism*
  • Protein Binding
  • Protein Unfolding*
  • Spectrum Analysis
  • von Willebrand Factor / metabolism

Substances

  • Platelet Glycoprotein GPIb-IX Complex
  • adhesion receptor
  • von Willebrand Factor
  • Leucine