Ca2+-saturated calmodulin binds tightly to the N-terminal domain of A-type fibroblast growth factor homologous factors.
Saved in:
| Title: | Ca2+-saturated calmodulin binds tightly to the N-terminal domain of A-type fibroblast growth factor homologous factors. |
|---|---|
| Authors: | Mahling, Ryan1, Rahlf, Cade R.1, Hansen, Samuel C.1, Hayden, Matthew R.1, Shea, Madeline A.1 madeline-shea@uiowa.edu |
| Source: | Journal of Biological Chemistry. Jan-Jun2021, Vol. 296, p1-23. 23p. |
| Subjects: | Calmodulin, Fibroblast growth factors, Sodium channels, Fluorescence spectroscopy, Binding sites, Net Asset Value |
| Abstract: | Voltage-gated sodium channels (Navs) are tightly regulated by multiple conserved auxiliary proteins, including the four fibroblast growth factor homologous factors (FGFs), which bind the Nav EF-hand like domain (EFL), and calmodulin (CaM), a multifunctional messenger protein that binds the NaV IQ motif. The EFL domain and IQ motif are contiguous regions of NaV cytosolic C-terminal domains (CTD), placing CaM and FGF in close proximity. However, whether the FGFs and CaM act independently, directly associate, or operate through allosteric interactions to regulate channel function is unknown. Titrations monitored by steady-state fluorescence spectroscopy, structural studies with solution NMR, and computational modeling demonstrated for the first time that both domains of (Ca2+)4-CaM (but not apo CaM) directly bind two sites in the N-terminal domain (NTD) of A-type FGF splice variants (FGF11A, FGF12A, FGF13A, and FGF14A) with high affinity. The weaker of the (Ca2+)4-CaM-binding sites was known via electrophysiology to have a role in long-term inactivation of the channel but not known to bind CaM. FGF12A binding to a complex of CaM associated with a fragment of the NaV1.2 CTD increased the Ca2+-binding affinity of both CaM domains, consistent with (Ca2+)4-CaM interacting preferentially with its higher-affinity site in the FGF12A NTD. Thus, A-type FGFs can compete with NaV IQ motifs for (Ca2+)4-CaM. During spikes in the cytosolic Ca2+ concentration that accompany an action potential, CaM may translocate from the NaV IQ motif to the FGF NTD, or the A-type FGF NTD may recruit a second molecule of CaM to the channel. [ABSTRACT FROM AUTHOR] |
| Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Engineering Source |
| FullText | Text: Availability: 0 |
|---|---|
| Header | DbId: egs DbLabel: Engineering Source An: 151446687 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
| IllustrationInfo | |
| Items | – Name: Title Label: Title Group: Ti Data: Ca<superscript>2+</superscript>-saturated calmodulin binds tightly to the N-terminal domain of A-type fibroblast growth factor homologous factors. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Mahling%2C+Ryan%22">Mahling, Ryan</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Rahlf%2C+Cade+R%2E%22">Rahlf, Cade R.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Hansen%2C+Samuel+C%2E%22">Hansen, Samuel C.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Hayden%2C+Matthew+R%2E%22">Hayden, Matthew R.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Shea%2C+Madeline+A%2E%22">Shea, Madeline A.</searchLink><relatesTo>1</relatesTo><i> madeline-shea@uiowa.edu</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. Jan-Jun2021, Vol. 296, p1-23. 23p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Calmodulin%22">Calmodulin</searchLink><br /><searchLink fieldCode="DE" term="%22Fibroblast+growth+factors%22">Fibroblast growth factors</searchLink><br /><searchLink fieldCode="DE" term="%22Sodium+channels%22">Sodium channels</searchLink><br /><searchLink fieldCode="DE" term="%22Fluorescence+spectroscopy%22">Fluorescence spectroscopy</searchLink><br /><searchLink fieldCode="DE" term="%22Binding+sites%22">Binding sites</searchLink><br /><searchLink fieldCode="DE" term="%22Net+Asset+Value%22">Net Asset Value</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Voltage-gated sodium channels (Navs) are tightly regulated by multiple conserved auxiliary proteins, including the four fibroblast growth factor homologous factors (FGFs), which bind the Nav EF-hand like domain (EFL), and calmodulin (CaM), a multifunctional messenger protein that binds the NaV IQ motif. The EFL domain and IQ motif are contiguous regions of NaV cytosolic C-terminal domains (CTD), placing CaM and FGF in close proximity. However, whether the FGFs and CaM act independently, directly associate, or operate through allosteric interactions to regulate channel function is unknown. Titrations monitored by steady-state fluorescence spectroscopy, structural studies with solution NMR, and computational modeling demonstrated for the first time that both domains of (Ca2+)4-CaM (but not apo CaM) directly bind two sites in the N-terminal domain (NTD) of A-type FGF splice variants (FGF11A, FGF12A, FGF13A, and FGF14A) with high affinity. The weaker of the (Ca2+)4-CaM-binding sites was known via electrophysiology to have a role in long-term inactivation of the channel but not known to bind CaM. FGF12A binding to a complex of CaM associated with a fragment of the NaV1.2 CTD increased the Ca2+-binding affinity of both CaM domains, consistent with (Ca2+)4-CaM interacting preferentially with its higher-affinity site in the FGF12A NTD. Thus, A-type FGFs can compete with NaV IQ motifs for (Ca2+)4-CaM. During spikes in the cytosolic Ca2+ concentration that accompany an action potential, CaM may translocate from the NaV IQ motif to the FGF NTD, or the A-type FGF NTD may recruit a second molecule of CaM to the channel. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
| PLink | https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=egs&AN=151446687 |
| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1016/j.jbc.2021.100458 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 23 StartPage: 1 Subjects: – SubjectFull: Calmodulin Type: general – SubjectFull: Fibroblast growth factors Type: general – SubjectFull: Sodium channels Type: general – SubjectFull: Fluorescence spectroscopy Type: general – SubjectFull: Binding sites Type: general – SubjectFull: Net Asset Value Type: general Titles: – TitleFull: Ca2+-saturated calmodulin binds tightly to the N-terminal domain of A-type fibroblast growth factor homologous factors. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Mahling, Ryan – PersonEntity: Name: NameFull: Rahlf, Cade R. – PersonEntity: Name: NameFull: Hansen, Samuel C. – PersonEntity: Name: NameFull: Hayden, Matthew R. – PersonEntity: Name: NameFull: Shea, Madeline A. IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 01 Text: Jan-Jun2021 Type: published Y: 2021 Identifiers: – Type: issn-print Value: 00219258 Numbering: – Type: volume Value: 296 Titles: – TitleFull: Journal of Biological Chemistry Type: main |
| ResultId | 1 |
