Molecular effects of calcium binding mutations in Marfan syndrome depend on domain context.
Mutations in the human fibrillin-1 (FBN-1) gene cause Marfan syndrome (MFS), an autosomal dominant disease of connective tissue. Fibrillin-1, a 350 kDa extracellular calcium binding protein, is a major structural component of 10-12 nm microfibrils and consists predominantly of two repeated module ty...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
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2000
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| _version_ | 1797060761381502976 |
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| author | McGettrick, A Knott, V Willis, A Handford, P |
| author_facet | McGettrick, A Knott, V Willis, A Handford, P |
| author_sort | McGettrick, A |
| collection | OXFORD |
| description | Mutations in the human fibrillin-1 (FBN-1) gene cause Marfan syndrome (MFS), an autosomal dominant disease of connective tissue. Fibrillin-1, a 350 kDa extracellular calcium binding protein, is a major structural component of 10-12 nm microfibrils and consists predominantly of two repeated module types: the calcium binding epidermal growth factor-like (cbEGF) domain and the transforming growth factor beta1 binding protein-like (TB) domain. A group of reported FBN-1 mutations is predicted to reduce calcium binding to cbEGF domains by removal of a side chain ligand for calcium. These mutations occur in two protein domain contexts, either in a cbEGF preceded by a TB domain or in a cbEGF preceded by another cbEGF domain. In this study we have used three proteases to probe structural changes caused by an N2144S MFS calcium binding mutation in a TB6-cbEGF32 and a cbEGF32-33 domain pair, and an N2183S mutation in the cbEGF32-33 pair. N-terminal sequence analysis of domain pairs digested in the presence and absence of calcium show that: (i) domain interactions between TB6 and cbEGF32 are calcium independent, despite the presence of a calcium binding site in cbEGF32; (ii) domain interactions between cbEGF32 and cbEGF33 are calcium dependent; and (iii) an N-->S mutation causes increased proteolytic susceptibility only when located in cbEGF33, consistent with a key role for interdomain calcium binding in rigidifying cbEGF domain linkages. These data demonstrate for the first time that the structural consequences of calcium binding mutations in fibrillin-1 cbEGF domains can be influenced by domain context. |
| first_indexed | 2024-03-06T20:21:28Z |
| format | Journal article |
| id | oxford-uuid:2decece3-7ee7-4372-9fd2-794fb60f5d3a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:21:28Z |
| publishDate | 2000 |
| record_format | dspace |
| spelling | oxford-uuid:2decece3-7ee7-4372-9fd2-794fb60f5d3a2022-03-26T12:46:01ZMolecular effects of calcium binding mutations in Marfan syndrome depend on domain context.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2decece3-7ee7-4372-9fd2-794fb60f5d3aEnglishSymplectic Elements at Oxford2000McGettrick, AKnott, VWillis, AHandford, PMutations in the human fibrillin-1 (FBN-1) gene cause Marfan syndrome (MFS), an autosomal dominant disease of connective tissue. Fibrillin-1, a 350 kDa extracellular calcium binding protein, is a major structural component of 10-12 nm microfibrils and consists predominantly of two repeated module types: the calcium binding epidermal growth factor-like (cbEGF) domain and the transforming growth factor beta1 binding protein-like (TB) domain. A group of reported FBN-1 mutations is predicted to reduce calcium binding to cbEGF domains by removal of a side chain ligand for calcium. These mutations occur in two protein domain contexts, either in a cbEGF preceded by a TB domain or in a cbEGF preceded by another cbEGF domain. In this study we have used three proteases to probe structural changes caused by an N2144S MFS calcium binding mutation in a TB6-cbEGF32 and a cbEGF32-33 domain pair, and an N2183S mutation in the cbEGF32-33 pair. N-terminal sequence analysis of domain pairs digested in the presence and absence of calcium show that: (i) domain interactions between TB6 and cbEGF32 are calcium independent, despite the presence of a calcium binding site in cbEGF32; (ii) domain interactions between cbEGF32 and cbEGF33 are calcium dependent; and (iii) an N-->S mutation causes increased proteolytic susceptibility only when located in cbEGF33, consistent with a key role for interdomain calcium binding in rigidifying cbEGF domain linkages. These data demonstrate for the first time that the structural consequences of calcium binding mutations in fibrillin-1 cbEGF domains can be influenced by domain context. |
| spellingShingle | McGettrick, A Knott, V Willis, A Handford, P Molecular effects of calcium binding mutations in Marfan syndrome depend on domain context. |
| title | Molecular effects of calcium binding mutations in Marfan syndrome depend on domain context. |
| title_full | Molecular effects of calcium binding mutations in Marfan syndrome depend on domain context. |
| title_fullStr | Molecular effects of calcium binding mutations in Marfan syndrome depend on domain context. |
| title_full_unstemmed | Molecular effects of calcium binding mutations in Marfan syndrome depend on domain context. |
| title_short | Molecular effects of calcium binding mutations in Marfan syndrome depend on domain context. |
| title_sort | molecular effects of calcium binding mutations in marfan syndrome depend on domain context |
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