BibTex format
@article{Lau:2026,
author = {Lau, R and Giblin, S and Sugar, A and Di, Maio A and Tassinie, G and Huse, K and Chorev, D and Chen, Y and Wu, G and Berg, Huemer C and Seung, YK and Matthewsa, J and Muloud, B and Chen, L and McKenna, S and Xu, Y and Massai, L and Muzzie, C and Ferhatie, X and Necchie, F and Gomes, Moriel D and Feizi, T and James, P and Sriskandan, S and Matthews, S},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
title = {SpyCEP dismantles neutrophil immunity via disorder-drivenchemokine remodeling and GAG targeting},
year = {2026}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - Streptococcus pyogenes (Group A Streptococcus; GAS) employs sophisticated virulence strategies to evade human immunity, including secretion of the cell envelope protease SpyCEP, which cleaves and inactivates key neutrophilattracting chemokines such as CXCL8. Here, we integrate cryoelectron microscopy (cryoEM), nuclear magnetic resonance (NMR) spectroscopy, and native mass spectrometry (MS) 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 disordermediated 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 to recruit SpyCEP and maximize encounters with GAGenriched 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 new avenues for antivirulence therapies and vaccine strategies targeting SpyCEP.
AU - Lau,R
AU - Giblin,S
AU - Sugar,A
AU - Di,Maio A
AU - Tassinie,G
AU - Huse,K
AU - Chorev,D
AU - Chen,Y
AU - Wu,G
AU - Berg,Huemer C
AU - Seung,YK
AU - Matthewsa,J
AU - Muloud,B
AU - Chen,L
AU - McKenna,S
AU - Xu,Y
AU - Massai,L
AU - Muzzie,C
AU - Ferhatie,X
AU - Necchie,F
AU - Gomes,Moriel D
AU - Feizi,T
AU - James,P
AU - Sriskandan,S
AU - Matthews,S
PY - 2026///
SN - 0027-8424
TI - SpyCEP dismantles neutrophil immunity via disorder-drivenchemokine remodeling and GAG targeting
T2 - Proceedings of the National Academy of Sciences of the United States of America
ER -