To the top

Page Manager: Webmaster
Last update: 9/11/2012 3:13 PM

Tell a friend about this page
Print version

Identification of Residue… - University of Gothenburg, Sweden Till startsida
Sitemap
To content Read more about how we use cookies on gu.se

Identification of Residues Critical for FPR2 Activation by the Cryptic Peptide Mitocryptide-2 Originating from the Mitochondrial DNA-Encoded Cytochrome b.

Journal article
Authors Simon Lind
Michael Gabl
André Holdfeldt
Jonas Mårtensson
Martina Sundqvist
Kodai Nishino
Claes Dahlgren
Hidehito Mukai
Huamei Forsman
Published in Journal of immunology (Baltimore, Md. : 1950)
Volume 202
Issue 9
Pages 2710-2719
ISSN 1550-6606
Publication year 2019
Published at Institute of Medicine, Department of Rheumatology and Inflammation Research
Pages 2710-2719
Language en
Links dx.doi.org/10.4049/jimmunol.1900060
www.ncbi.nlm.nih.gov/entrez/query.f...
Keywords Neutrophils, mtDNA, NADPH oxidase, SAR, MCT-2,
Subject categories Medical cell biology, Immunobiology

Abstract

Similar to bacteria, synthesis of mitochondrial DNA-encoded proteins requires an N-formylated methionine to initiate translation. Thus, the N-formylated methionine peptides originating from mitochondria should be recognized as danger signals. To date, only one such peptide, denoted as mitocryptide-2 (MCT-2), originating from the N-terminal of the mitochondrial cytochrome b, has been isolated from mammalian tissues. Human neutrophils express FPR1 and FPR2 that detect formyl peptides, and the precise structural determinants for receptor recognition remain to be elucidated. MCT-2 is known to activate neutrophils through FPR2 but not FPR1. The aim of this study was to elucidate the structural determinants of importance for receptor preference and human neutrophil activation in MCT-2 by generating a series of MCT-2 variants. We show that there is an absolute requirement for the N-formyl group and the side chain of Met1 at position 1 of MCT-2 but also the C terminus is of importance for MCT-2 activity. We also uncovered individual side chains that positively contribute to MCT-2 activity as well as those suppressed in the response. The MCT-2 peptide and its two polymorphic variants ([Thr7]MCT-2 and [Ser8]MCT-2) all activated neutrophils, but MCT-2 containing Ile7 and Asn8 was the most potent. We also show that some peptide variants displayed a biased FPR2-signaling property related to NADPH oxidase activation and β-arrestin recruitment, respectively. In conclusion, we disclose several critical elements in MCT-2 that are required for neutrophil activation and disclose structural insights into how FPR2 recognition of this mitochondrial DNA-derived peptide may increase our understanding of the role of FPR2 in aseptic inflammation.

Page Manager: Webmaster|Last update: 9/11/2012
Share:

The University of Gothenburg uses cookies to provide you with the best possible user experience. By continuing on this website, you approve of our use of cookies.  What are cookies?