Sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor TIMP-3.
Tissue inhibitor of metalloproteinase 3 (TIMP-3) is an important regulator of extracellular matrix (ECM) turnover. TIMP-3 binds to sulfated ECM glycosaminoglycans or is endocytosed by cells via low-density lipoprotein receptor-related protein 1 (LRP-1). Here, we report that heparan sulfate (HS) and...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2014
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| _version_ | 1797093452611059712 |
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| author | Troeberg, L Lazenbatt, C Anower-E-Khuda, M Freeman, C Federov, O Habuchi, H Habuchi, O Kimata, K Nagase, H |
| author_facet | Troeberg, L Lazenbatt, C Anower-E-Khuda, M Freeman, C Federov, O Habuchi, H Habuchi, O Kimata, K Nagase, H |
| author_sort | Troeberg, L |
| collection | OXFORD |
| description | Tissue inhibitor of metalloproteinase 3 (TIMP-3) is an important regulator of extracellular matrix (ECM) turnover. TIMP-3 binds to sulfated ECM glycosaminoglycans or is endocytosed by cells via low-density lipoprotein receptor-related protein 1 (LRP-1). Here, we report that heparan sulfate (HS) and chondroitin sulfate E (CSE) selectively regulate postsecretory trafficking of TIMP-3 by inhibiting its binding to LRP-1. HS and CSE also increased TIMP-3 affinity for glycan-binding metalloproteinases, such as adamalysin-like metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), by reducing the dissociation rate constants. The sulfation pattern was crucial for these activities because monosulfated or truncated heparin had a reduced ability to bind to TIMP-3 and increase its affinity for ADAMTS-5. Therefore, sulfation of ECM glycans regulates the levels and inhibitory activity of TIMP-3 and modulates ECM turnover, and small mimicries of sulfated glycans may protect the tissue from the excess destruction seen in diseases such as osteoarthritis, cancer, and atherosclerosis. |
| first_indexed | 2024-03-07T04:00:37Z |
| format | Journal article |
| id | oxford-uuid:c471c38f-4ea7-4517-96ca-ed93d50aeeb1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:00:37Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:c471c38f-4ea7-4517-96ca-ed93d50aeeb12022-03-27T06:23:31ZSulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor TIMP-3.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:c471c38f-4ea7-4517-96ca-ed93d50aeeb1EnglishSymplectic Elements at Oxford2014Troeberg, LLazenbatt, CAnower-E-Khuda, MFreeman, CFederov, OHabuchi, HHabuchi, OKimata, KNagase, HTissue inhibitor of metalloproteinase 3 (TIMP-3) is an important regulator of extracellular matrix (ECM) turnover. TIMP-3 binds to sulfated ECM glycosaminoglycans or is endocytosed by cells via low-density lipoprotein receptor-related protein 1 (LRP-1). Here, we report that heparan sulfate (HS) and chondroitin sulfate E (CSE) selectively regulate postsecretory trafficking of TIMP-3 by inhibiting its binding to LRP-1. HS and CSE also increased TIMP-3 affinity for glycan-binding metalloproteinases, such as adamalysin-like metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), by reducing the dissociation rate constants. The sulfation pattern was crucial for these activities because monosulfated or truncated heparin had a reduced ability to bind to TIMP-3 and increase its affinity for ADAMTS-5. Therefore, sulfation of ECM glycans regulates the levels and inhibitory activity of TIMP-3 and modulates ECM turnover, and small mimicries of sulfated glycans may protect the tissue from the excess destruction seen in diseases such as osteoarthritis, cancer, and atherosclerosis. |
| spellingShingle | Troeberg, L Lazenbatt, C Anower-E-Khuda, M Freeman, C Federov, O Habuchi, H Habuchi, O Kimata, K Nagase, H Sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor TIMP-3. |
| title | Sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor TIMP-3. |
| title_full | Sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor TIMP-3. |
| title_fullStr | Sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor TIMP-3. |
| title_full_unstemmed | Sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor TIMP-3. |
| title_short | Sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor TIMP-3. |
| title_sort | sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor timp 3 |
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