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Characterization of an Extensive Interface on Vitronectin for Binding to Plasminogen Activator Inhibitor-1: Adoption of Structure in an Intrinsically Disordered Region

Published

Author(s)

Letitia O. Puster, Christopher B. Stanley, Vladmir N. Uversky, Joseph E. Curtis, Susan T. Krueger, Yuzhuo Chu, Cynthia B. Peterson

Abstract

Small-angle neutron scattering (SANS) measurements were used to characterize vitronectin, a protein found in human plasma and tissues that functions in regulating cell adhesion and migration, as well as proteolytic cascades that affect blood coagulation, fibrinolysis, and pericellular proteolysis. We focused on a region of the structure that remains uncharacterized from previous x-ray scattering, NMR and computational modeling approaches. This region, which bridges the N-terminal somatomedin B (SMB) domain with a large central β-propeller domain of vitronectin, appears unstructured and has characteristics of an intrinsically disordered domain (IDD). The effect of osmolytes was studied by circular dichroism (CD) and SANS to explore the potential of the IDD to undergo a disorder-to-order transition. CD resutls suggest that the IDD domain favors a more ordered structure under osmotic pressure; SANS measurements indicate a reduction on the radius of gyration (Rg) and a more compact fold of the IDD under osmotic stress. To test whether PAI-1 binding is coupled to folding within the IDD structure, a series of contrast variation SANS experiments were performed on a vitronectin fragment comprised of the N-terminal SMB domain and IDD (denoted SMD-IDD) in complex with PAI-1. Ensemble Optimization Method (EOM) analysis of the SANS data confirms that SMB-IDD adopts a more compact structure when bound to PAI-1. Models for the PAI-1:SMB-IDD complex suggest that the IDD folds to an ordered coil structure that provides an interaction surface outside of the primary PAI-1 binding site in the SMB. This site within the IDD is complementary to features of a more extensive binding surface on PAI-1 that has been described (Schar, C.R., Jensen, J.K., Christensen, A., Blouse, G.E., Andreasen, P.A., and Peterson, C.B. *2008) J.Biol.Chem. 283, 28487-28496). The coupled folding and binding in this region is proposed to lead to the assembly of higher-order structures of PAI-1 and vitronectin commonly found in tissues.
Citation
Biochemistry
Volume
58
Issue
51

Keywords

Vitronectin, PAI-1, Intrinsic Disorder, SANS

Citation

Puster, L. , Stanley, C. , Uversky, V. , Curtis, J. , Krueger, S. , Chu, Y. and Peterson, C. (2019), Characterization of an Extensive Interface on Vitronectin for Binding to Plasminogen Activator Inhibitor-1: Adoption of Structure in an Intrinsically Disordered Region, Biochemistry, [online], https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=928270 (Accessed June 21, 2024)

Issues

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Created December 23, 2019, Updated October 12, 2021