Force-Induced Unfolding of Leucine-Rich Repeats of Glycoprotein Ib? Strengthens Ligand Interaction.

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 Ib? (GPIb?), a demonstrated mechanoreceptor with known crystal structures for the N-terminal domain (GPIb?N), 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 GPIb?N starts with LRR2-4 and propagates to other LRRs. Importantly, force-dependent lifetimes of individual VWF-A1 bonds with GPIb? are prolonged after LRR unfolding. Enhancement of protein-protein interactions by force-induced LRR unfolding may be a phenomenon of interest in biology.

SUBMITTER: Ju L 

PROVIDER: S-EPMC4643204 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature