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Crystal structure of ADAMTS13 CUB domains reveals their role in global latency
ADAMTS13 is a plasma metalloprotease that is essential for the regulation of von Willebrand factor (VWF) function, mediator of platelet recruitment to sites of blood vessel damage. ADAMTS13 function is dynamically regulated by structural changes induced by VWF binding that convert it from a latent t...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051872/ https://www.ncbi.nlm.nih.gov/pubmed/33863735 http://dx.doi.org/10.1126/sciadv.abg4403 |
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author | Kim, H. J. Xu, Y. Petri, A. Vanhoorelbeke, K. Crawley, J. T. B. Emsley, J. |
author_facet | Kim, H. J. Xu, Y. Petri, A. Vanhoorelbeke, K. Crawley, J. T. B. Emsley, J. |
author_sort | Kim, H. J. |
collection | PubMed |
description | ADAMTS13 is a plasma metalloprotease that is essential for the regulation of von Willebrand factor (VWF) function, mediator of platelet recruitment to sites of blood vessel damage. ADAMTS13 function is dynamically regulated by structural changes induced by VWF binding that convert it from a latent to active conformation. ADAMTS13 global latency is manifest by the interaction of its C-terminal CUB1-2 domains with its central Spacer domain. We resolved the crystal structure of the ADAMTS13 CUB1-2 domains revealing a previously unreported configuration for the tandem CUB domains. Docking simulations between the CUB1-2 domains with the Spacer domain in combination with enzyme kinetic functional characterization of ADAMTS13 CUB domain mutants enabled the mapping of the CUB1-2 domain site that binds the Spacer domain. Together, these data reveal the molecular basis of the ADAMTS13 Spacer-CUB interaction and the control of ADAMTS13 global latency. |
format | Online Article Text |
id | pubmed-8051872 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-80518722021-04-26 Crystal structure of ADAMTS13 CUB domains reveals their role in global latency Kim, H. J. Xu, Y. Petri, A. Vanhoorelbeke, K. Crawley, J. T. B. Emsley, J. Sci Adv Research Articles ADAMTS13 is a plasma metalloprotease that is essential for the regulation of von Willebrand factor (VWF) function, mediator of platelet recruitment to sites of blood vessel damage. ADAMTS13 function is dynamically regulated by structural changes induced by VWF binding that convert it from a latent to active conformation. ADAMTS13 global latency is manifest by the interaction of its C-terminal CUB1-2 domains with its central Spacer domain. We resolved the crystal structure of the ADAMTS13 CUB1-2 domains revealing a previously unreported configuration for the tandem CUB domains. Docking simulations between the CUB1-2 domains with the Spacer domain in combination with enzyme kinetic functional characterization of ADAMTS13 CUB domain mutants enabled the mapping of the CUB1-2 domain site that binds the Spacer domain. Together, these data reveal the molecular basis of the ADAMTS13 Spacer-CUB interaction and the control of ADAMTS13 global latency. American Association for the Advancement of Science 2021-04-16 /pmc/articles/PMC8051872/ /pubmed/33863735 http://dx.doi.org/10.1126/sciadv.abg4403 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Kim, H. J. Xu, Y. Petri, A. Vanhoorelbeke, K. Crawley, J. T. B. Emsley, J. Crystal structure of ADAMTS13 CUB domains reveals their role in global latency |
title | Crystal structure of ADAMTS13 CUB domains reveals their role in global latency |
title_full | Crystal structure of ADAMTS13 CUB domains reveals their role in global latency |
title_fullStr | Crystal structure of ADAMTS13 CUB domains reveals their role in global latency |
title_full_unstemmed | Crystal structure of ADAMTS13 CUB domains reveals their role in global latency |
title_short | Crystal structure of ADAMTS13 CUB domains reveals their role in global latency |
title_sort | crystal structure of adamts13 cub domains reveals their role in global latency |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051872/ https://www.ncbi.nlm.nih.gov/pubmed/33863735 http://dx.doi.org/10.1126/sciadv.abg4403 |
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