title: Force-Induced Unfolding of Leucine-Rich Repeats of Glycoprotein Ibα 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 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.
authors.affiliation: Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia; Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia; Heart Research Institute, Camperdown, New South Wales, Australia; Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia. Electronic address: arnold.ju@sydney.edu.au.
authors.forename: Lining
authors.initials: L
authors.lastname: Ju
authors.affiliation: Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jizhong
authors.initials: J
authors.lastname: Lou
authors.affiliation: Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia; Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Quantum Beam Science Directorate, Japan Atomic Energy Agency, Kizugawa, Kyoto, Japan.
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Li
authors.affiliation: Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia; Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia; Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia. Electronic address: cheng.zhu@bme.gatech.edu.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
mesh_terms: D007930:Leucine / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D011485:Protein Binding; D058767:Protein Unfolding; D013057:Spectrum Analysis; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor; D014841:von Willebrand Factor; D007930:Leucine