Imperial College London
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Dr Josefin Ahnström

Faculty of Medicine, Department of Immunology and Inflammation

Senior Lecturer in Haematology
 
 
 
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Contact

 

+44 (0)20 3313 4236j.ahnstrom

 
 
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Location

 

5S5Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Minns:2023:10.1016/j.jbc.2023.103048,
author = {Minns, AF and Qi, Y and Yamamoto, K and Lee, K and Ahnström, J and Santamaria, S},
doi = {10.1016/j.jbc.2023.103048},
journal = {Journal of Biological Chemistry},
title = {The C-terminal domains of ADAMTS1 contain exosites involved in its proteoglycanase activity},
url = {http://dx.doi.org/10.1016/j.jbc.2023.103048},
volume = {299},
year = {2023}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - A disintegrin-like and metalloproteinase with thrombospondin type 1 motifs (ADAMTS1) is a protease involved in fertilization, cancer, cardiovascular development, and thoracic aneurysms. Proteoglycans such as versican and aggrecan have been identified as ADAMTS1 substrates, and Adamts1 ablation in mice typically results in versican accumulation; however, previous qualitative studies have suggested that ADAMTS1 proteoglycanase activity is weaker than that of other family members such as ADAMTS4 and ADAMTS5. Here, we investigated the functional determinants of ADAMTS1 proteoglycanase activity. We found that ADAMTS1 versicanase activity is approximately 1000-fold lower than ADAMTS5 and 50-fold lower than ADAMTS4 with a kinetic constant (kcat/Km) of 3.6 × 103 M-1 s-1 against full-length versican. Studies on domain-deletion variants identified the spacer and cysteine-rich domains as major determinants of ADAMTS1 versicanase activity. Additionally, we confirmed that these C-terminal domains are involved in the proteolysis of aggrecan as well as biglycan, a small leucine-rich proteoglycan. Glutamine scanning mutagenesis of exposed positively charged residues on the spacer domain loops and loop substitution with ADAMTS4 identified clusters of substrate-binding residues (exosites) in β3-β4 (R756Q/R759Q/R762Q), β9-β10 (residues 828-835), and β6-β7 (K795Q) loops. This study provides a mechanistic foundation for understanding the interactions between ADAMTS1 and its proteoglycan substrates and paves the way for development of selective exosite modulators of ADAMTS1 proteoglycanase activity.
AU  - Minns,AF
AU  - Qi,Y
AU  - Yamamoto,K
AU  - Lee,K
AU  - Ahnström,J
AU  - Santamaria,S
DO  - 10.1016/j.jbc.2023.103048
PY  - 2023///
SN  - 0021-9258
TI  - The C-terminal domains of ADAMTS1 contain exosites involved in its proteoglycanase activity
T2  - Journal of Biological Chemistry
UR  - http://dx.doi.org/10.1016/j.jbc.2023.103048
UR  - https://www.ncbi.nlm.nih.gov/pubmed/36813235
UR  - http://hdl.handle.net/10044/1/103217
VL  - 299
ER  -
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