SpyCEP dismantles neutrophil immunity via disorder-driven chemokine remodeling and GAG targeting
Abstract
Streptococcus pyogenes (Group A Streptococcus ) employs sophisticated virulence strategies to evade human immunity, including secretion of the cell envelope protease SpyCEP, which cleaves and inactivates key neutrophil-attracting chemokines such as CXCL8. Here, we integrate cryo-electron microscopy, NMR spectroscopy, and native mass spectrometry to investigate how SpyCEP disrupts CXCL8 function. We demonstrate that a disordered aromatic and acidic region within the cleaved autocatalytic maturation loop (CAML) of SpyCEP mimics receptor N-domains and binds an allosteric site on CXCL8. The resulting interaction forms a dynamic fuzzy complex and is coupled to dimer dissociation, consistent with enhanced access to the cleavage site. This disorder-mediated substrate engagement differs from classical protease mechanisms that rely on rigid recognition interfaces. Additionally, glycan microarray and NMR analyses show that the CAML region mediates glycosaminoglycan (GAG) binding, suggesting a means for SpyCEP to maximize encounters with GAG-enriched CXCL8 reservoirs. Together, these findings provide a structural and biophysical framework for understanding how SpyCEP combines substrate engagement with GAG targeting to dismantle chemokine gradients and inhibit neutrophil recruitment. More broadly, this work highlights the role of intrinsic disorder in protease recognition and suggests avenues for anti-virulence therapies and vaccine strategies targeting SpyCEP.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (26)
Rikin J. Lau
Department of Life Sciences, Imperial College London
Sean P. Giblin
National Heart and Lung Institute, Imperial College London
Andra Sugar
Department of Life Sciences, Imperial College London
Antonio Di Maio
Glycosciences Laboratory, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London
Giulio Tassini
GlaxoSmithKline Vaccines Institute for Global Health
Kristin Huse
Centre for Bacterial Resistance Biology, Imperial College London
Dror Chorev
CTM Technologies and Materials Ltd.
Yuan Chen
School of Chemical and Biomolecular Engineering
Grace Ho-Yan Wu
Department of Life Sciences, Imperial College London
Camilla Berg Huemer
Department of Life Sciences, Imperial College London
Seung Yon Kim
Department of Life Sciences, Imperial College London
Jayden Matthews
Department of Life Sciences, Imperial College London
Bel Muloud
Department of Life Sciences, Imperial College London
Lu Chen
Sophie McKenna
Yingqi Xu
Department of Life Sciences, Imperial College London
Luisa Massai
GlaxoSmithKline Vaccines Institute for Global Health
Chiara Muzzi
GlaxoSmithKline Vaccines Institute for Global Health
Xhenti Ferhati
GlaxoSmithKline Vaccines Institute for Global Health
Francesca Necchi
GSK Vaccines Institute for Global Health
Danilo Gomes Moriel
GlaxoSmithKline Vaccines Institute for Global Health
Ten Feizi
Glycosciences Laboratory, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London
Yan Liu
James E. Pease
National Heart and Lung Institute, Imperial College London
Shiranee Sriskandan
Steve Matthews
Department of Life Sciences, Imperial College London