A Structural Basis for Inhibition of the Complement Initiator Protease C1r by Lyme Disease Spirochetes
Year: 2021
Type: article
Abstract: , the causative agent of Lyme disease. Lyme disease spirochetes express nearly a dozen outer surface lipoproteins that bind complement components and interfere with their native activities. Among these, BBK32 is unique in its selective inhibition of the classical pathway. BBK32 blocks activation of this pathway by selectively binding and inhibiting the C1r serine protease of the first component of complement, C1. To understand the structural basis for BBK32-mediated C1r inhibition, we performed crystallography and size-exclusion chromatography-coupled small angle X-ray scattering experiments, which revealed a molecular model of BBK32-C in complex with activated human C1r. Structure-guided site-directed mutagenesis was combined with surface plasmon resonance binding experiments and assays of complement function to validate the predicted molecular interface. Analysis of the structures shows that BBK32 inhibits activated forms of C1r by occluding substrate interaction subsites (i.e., S1 and S1') and reveals a surprising role for C1r B loop-interacting residues for full inhibitory activity of BBK32. The studies reported in this article provide for the first time (to our knowledge) a structural basis for classical pathway-specific inhibition by a human pathogen.
Source: The Journal of Immunology
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
Awards: G1235180860, G1286236842, G1286251239, G1313983767, G1756342139, G1767990418, G18202666, G1940553382, G2123841078, G2202731092, G2539837713, G2618837358, G2638771445, Classical Complement Pathway Evasion Mechanisms of Lyme Disease Spirochetes, G30714459, G3083819904, A Pixel Array Detector System for Small Angle X-ray Scattering, Virulence Mechanisms of Multifunctional Borrelial Proteins, G334911014, G419881185, Virulence Mechanisms of Multifunctional Borrelial Proteins, G42916606, G4501827968, G498139845, G572720644, G5888245624, G6206027980, G650090426, G6652958823, G7583586053, G8229677252, G8327918176, ALS Efficiently Networking Advanced Beam Line Experiments (ALS-ENABLE), G969889393
OpenAlex ID: W3213333529