Structure of three tandem filamin domains reveals auto-inhibition of ligand binding
Human filamins are large actin-crosslinking proteins composed of an N-terminal actin-binding domain followed by 24 Ig-like domains (IfFLNs), which interact with numerous transmembrane receptors and cytosolic signaling proteins. Here we report the 2.5 Å resolution structure of a three-domain fragment...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Nature Publishing Group
2007
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| Subjects: |
| _version_ | 1826273815571726336 |
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| author | Lad, Y Kiema, T Jiang, P Pentikäinen, O Coles, C Campbell, I Calderwood, D Ylänne, J |
| author2 | European Molecular Biology Organization |
| author_facet | European Molecular Biology Organization Lad, Y Kiema, T Jiang, P Pentikäinen, O Coles, C Campbell, I Calderwood, D Ylänne, J |
| author_sort | Lad, Y |
| collection | OXFORD |
| description | Human filamins are large actin-crosslinking proteins composed of an N-terminal actin-binding domain followed by 24 Ig-like domains (IfFLNs), which interact with numerous transmembrane receptors and cytosolic signaling proteins. Here we report the 2.5 Å resolution structure of a three-domain fragment of human filamin A (IgFLNa19-21). The structure reveals an unexpected domain arrangemetn, with IgFLNa20 partially unfolded bringing IgFLNa21 into close proximity to IgFLNa19. Notably the N-terminus of IgFLNa20 forms a β-strand that associates with the CD face of IgFLNa21 and occupies the binding site for integrin adhesion receptors. Disruption of this IgFLNa20-IgFLNa21 interaction enhances filamin binding to integrin β-tails. Structural and functional analysis of other IgFLN domains suggests that auto-inhibition by adjacent IgFLN domains may be a general mechanism controlling filamin-ligand interactions. This can explain the increased integrin binding of filamin splice variants and provides a mechanism by which ligand binding might impact filamin structure. |
| first_indexed | 2024-03-06T22:33:57Z |
| format | Journal article |
| id | oxford-uuid:593888b0-7bdb-4588-a3df-8acc77db2121 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:33:57Z |
| publishDate | 2007 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:593888b0-7bdb-4588-a3df-8acc77db21212022-03-26T17:08:35ZStructure of three tandem filamin domains reveals auto-inhibition of ligand bindingJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:593888b0-7bdb-4588-a3df-8acc77db2121BiochemistryEnglishOxford University Research Archive - ValetNature Publishing Group2007Lad, YKiema, TJiang, PPentikäinen, OColes, CCampbell, ICalderwood, DYlänne, JEuropean Molecular Biology OrganizationHuman filamins are large actin-crosslinking proteins composed of an N-terminal actin-binding domain followed by 24 Ig-like domains (IfFLNs), which interact with numerous transmembrane receptors and cytosolic signaling proteins. Here we report the 2.5 Å resolution structure of a three-domain fragment of human filamin A (IgFLNa19-21). The structure reveals an unexpected domain arrangemetn, with IgFLNa20 partially unfolded bringing IgFLNa21 into close proximity to IgFLNa19. Notably the N-terminus of IgFLNa20 forms a β-strand that associates with the CD face of IgFLNa21 and occupies the binding site for integrin adhesion receptors. Disruption of this IgFLNa20-IgFLNa21 interaction enhances filamin binding to integrin β-tails. Structural and functional analysis of other IgFLN domains suggests that auto-inhibition by adjacent IgFLN domains may be a general mechanism controlling filamin-ligand interactions. This can explain the increased integrin binding of filamin splice variants and provides a mechanism by which ligand binding might impact filamin structure. |
| spellingShingle | Biochemistry Lad, Y Kiema, T Jiang, P Pentikäinen, O Coles, C Campbell, I Calderwood, D Ylänne, J Structure of three tandem filamin domains reveals auto-inhibition of ligand binding |
| title | Structure of three tandem filamin domains reveals auto-inhibition of ligand binding |
| title_full | Structure of three tandem filamin domains reveals auto-inhibition of ligand binding |
| title_fullStr | Structure of three tandem filamin domains reveals auto-inhibition of ligand binding |
| title_full_unstemmed | Structure of three tandem filamin domains reveals auto-inhibition of ligand binding |
| title_short | Structure of three tandem filamin domains reveals auto-inhibition of ligand binding |
| title_sort | structure of three tandem filamin domains reveals auto inhibition of ligand binding |
| topic | Biochemistry |
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