Imperial College London

DrDaphneStapels

Faculty of MedicineDepartment of Medicine

Honorary Research Associate
 
 
 
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Contact

 

d.stapels

 
 
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Location

 

Flowers buildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Stapels:2018:10.1002/pro.3342,
author = {Stapels, DAC and Woehl, JL and Milder, FJ and Tromp, AT and van, Batenburg AA and de, Graaf WC and Broll, SC and White, NM and Rooijakkers, SHM and Geisbrecht, BV},
doi = {10.1002/pro.3342},
journal = {Protein Sci},
pages = {509--522},
title = {Evidence for multiple modes of neutrophil serine protease recognition by the EAP family of Staphylococcal innate immune evasion proteins.},
url = {http://dx.doi.org/10.1002/pro.3342},
volume = {27},
year = {2018}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - Neutrophils contain high levels of chymotrypsin-like serine proteases (NSPs) within their azurophilic granules that have a multitude of functions within the immune system. In response, the pathogen Staphylococcus aureus has evolved three potent inhibitors (Eap, EapH1, and EapH2) that protect the bacterium as well as several of its secreted virulence factors from the degradative action of NSPs. We previously showed that these so-called EAP domain proteins represent a novel class of NSP inhibitors characterized by a non-covalent inhibitory mechanism and a distinct target specificity profile. Based upon high levels of structural homology amongst the EAP proteins and the NSPs, as well as supporting biochemical data, we predicted that the inhibited complex would be similar for all EAP/NSP pairs. However, we present here evidence that EapH1 and EapH2 bind the canonical NSP, Neutrophil Elastase (NE), in distinct orientations. We discovered that alteration of EapH1 residues at the EapH1/NE interface caused a dramatic loss of affinity and inhibition of NE, while mutation of equivalent positions in EapH2 had no effect on NE binding or inhibition. Surprisingly, mutation of residues in an altogether different region of EapH2 severely impacted both the NE binding and inhibitory properties of EapH2. Even though EapH1 and EapH2 bind and inhibit NE and a second NSP, Cathepsin G, equally well, neither of these proteins interacts with the structurally related, but non-proteolytic granule protein, azurocidin. These studies expand our understanding of EAP/NSP interactions and suggest that members of this immune evasion protein family are capable of diverse target recognition modes.
AU - Stapels,DAC
AU - Woehl,JL
AU - Milder,FJ
AU - Tromp,AT
AU - van,Batenburg AA
AU - de,Graaf WC
AU - Broll,SC
AU - White,NM
AU - Rooijakkers,SHM
AU - Geisbrecht,BV
DO - 10.1002/pro.3342
EP - 522
PY - 2018///
SP - 509
TI - Evidence for multiple modes of neutrophil serine protease recognition by the EAP family of Staphylococcal innate immune evasion proteins.
T2 - Protein Sci
UR - http://dx.doi.org/10.1002/pro.3342
UR - https://www.ncbi.nlm.nih.gov/pubmed/29114958
VL - 27
ER -