Tyrosine-sulfated dermatopontin shares multiple binding sites and recognition determinants on triple-helical collagens with proteins implicated in cell adhesion and collagen folding, fibrillogenesis, cross-linking, and degradation

Morten M. Jensen, Arkadiusz Bonna, Sigurd J. Frederiksen, Samir W. Hamaia, Peter Højrup, Richard W. Farndale, Henrik Karring*

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Abstrakt

Dermatopontin (DPT), a small extracellular matrix protein that stimulates collagen fibrillogenesis, contains sulfotyrosine residues but neither its level of sulfation nor its binding sites on fibrillar collagens are known. Here, we discovered that DPT is present in a relatively high mass concentration (~ 0.02%) in porcine corneal stroma, from which we purified five DPT charge variants (A-E) containing up to six sulfations. The major variant (C), containing four sulfotyrosine residues, was used to locate binding sites for DPT on triple-helical collagens II and III using the Collagen Toolkits. DPT-binding loci included the triple helix crosslinking sites and collagenase cleavage site. We find that strong DPT-binding sites on triple-helical collagen comprise an arginine-rich, positively-charged sequence that also contains hydrophobic residues. This collagen-binding signature of DPT is similar to that of the chaperone HSP47. Thus, we propose that DPT assumes the role of HSP47 as a collagen chaperone during and after the secretion. Peptide II-44, harbouring the conserved collagenase cleavage site, shows the strongest DPT-binding of the Collagen Toolkit II peptides. Substituting any of the three arginine residues (R) with alanine in the sequence GLAGQRGIVGLOGQRGER of II-44 resulted in almost complete loss of DPT binding. Since osteogenesis imperfecta, spondyloepiphyseal dysplasia, and spondyloepimetaphyseal dysplasia congenita are associated with missense mutations that substitute the corresponding arginine residues in collagens alpha-1(I) and alpha-1(II), we suggest that disrupted DPT binding to fibrillar collagens may contribute to these connective tissue disorders. In conclusion, the present work provides a cornerstone for further elucidation of the role of DPT.

OriginalsprogEngelsk
Artikelnummer140771
TidsskriftBiochimica et Biophysica Acta - Proteins and Proteomics
Vol/bind1870
Udgave nummer5
ISSN1570-9639
DOI
StatusUdgivet - 1. maj 2022

Bibliografisk note

Funding Information:
This work was supported by the University of Southern Denmark (M. M. Jensen and H. Karring) and by a British Heart Foundation Programme grant, RG/15/4/31268 and Wellcome Trust Biomedical Resource grant 094470/Z/10/Z to R. W. Farndale. The Villum Center for Bioanalytical Sciences at the University of Southern Denmark is thanked for providing access to the mass spectrometers.

Funding Information:
R. W. Farndale reports financial support provided by British Heart Foundation Programme and Wellcome Trust Biomedical Resource . R. W. Farndale reports a relationship with CambCol Laboratories that includes: employment.

Funding Information:
R. W. Farndale reports financial support provided by British Heart Foundation Programme and Wellcome Trust Biomedical Resource. R. W. Farndale reports a relationship with CambCol Laboratories that includes: employment.This work was supported by the University of Southern Denmark (M. M. Jensen and H. Karring) and by a British Heart Foundation Programme grant, RG/15/4/31268 and Wellcome Trust Biomedical Resource grant 094470/Z/10/Z to R. W. Farndale. The Villum Center for Bioanalytical Sciences at the University of Southern Denmark is thanked for providing access to the mass spectrometers.

Publisher Copyright:
© 2022 The Authors

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