Arrhythmia-Associated Calmodulin E105A Mutation Alters the Binding Affinity of CaM to a Ryanodine Receptor 2 CaM-Binding Pocket
<p dir="ltr">Calmodulin (CaM) is a small, multifunctional calcium (Ca<sup>2+</sup>)-binding sensor that binds and regulates the open probability of cardiac ryanodine receptor 2 (RyR2) at both low and high cytosolic Ca<sup>2+</sup> concentrations. Recent isothe...
محفوظ في:
| المؤلف الرئيسي: | |
|---|---|
| مؤلفون آخرون: | , , , , , , |
| منشور في: |
2023
|
| الموضوعات: | |
| الوسوم: |
إضافة وسم
لا توجد وسوم, كن أول من يضع وسما على هذه التسجيلة!
|
| _version_ | 1864513531028701184 |
|---|---|
| author | Angelos Thanassoulas (2822861) |
| author2 | Maria Theodoridou (33087) Laila Barrak (17714490) Emna Riguene (17714493) Tamader Alyaarabi (17714496) Mohamed A. Elrayess (7956179) F. Anthony Lai (17714499) Michail Nomikos (17563188) |
| author2_role | author author author author author author author |
| author_facet | Angelos Thanassoulas (2822861) Maria Theodoridou (33087) Laila Barrak (17714490) Emna Riguene (17714493) Tamader Alyaarabi (17714496) Mohamed A. Elrayess (7956179) F. Anthony Lai (17714499) Michail Nomikos (17563188) |
| author_role | author |
| dc.creator.none.fl_str_mv | Angelos Thanassoulas (2822861) Maria Theodoridou (33087) Laila Barrak (17714490) Emna Riguene (17714493) Tamader Alyaarabi (17714496) Mohamed A. Elrayess (7956179) F. Anthony Lai (17714499) Michail Nomikos (17563188) |
| dc.date.none.fl_str_mv | 2023-10-26T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.3390/ijms242115630 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Arrhythmia-Associated_Calmodulin_E105A_Mutation_Alters_the_Binding_Affinity_of_CaM_to_a_Ryanodine_Receptor_2_CaM-Binding_Pocket/24921522 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Cardiovascular medicine and haematology Medical physiology Chemical sciences Medicinal and biomolecular chemistry calmodulin ryanodine receptor RyR2 arrhythmias cardiac disease |
| dc.title.none.fl_str_mv | Arrhythmia-Associated Calmodulin E105A Mutation Alters the Binding Affinity of CaM to a Ryanodine Receptor 2 CaM-Binding Pocket |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Calmodulin (CaM) is a small, multifunctional calcium (Ca<sup>2+</sup>)-binding sensor that binds and regulates the open probability of cardiac ryanodine receptor 2 (RyR2) at both low and high cytosolic Ca<sup>2+</sup> concentrations. Recent isothermal titration calorimetry (ITC) studies of a number of peptides that correspond to different regions of human RyR2 showed that two regions of human RyR2 (3584-3602aa and 4255-4271aa) bind with high affinity to CaM, suggesting that these two regions might contribute to a putative RyR2 intra-subunit CaM-binding pocket. Moreover, a previously characterized de novo long QT syndrome (LQTS)-associated missense CaM mutation (E105A) which was identified in a 6-year-old boy, who experienced an aborted first episode of cardiac arrest revealed that this mutation dysregulates normal cardiac function in zebrafish by a complex mechanism that involves alterations in both CaM-Ca<sup>2+</sup> and CaM-RyR2 interactions. Herein, to gain further insight into how the CaM E105A mutation leads to severe cardiac arrhythmia, we generated large quantities of recombinant CaMWT and CaME105A proteins. We then performed ITC experiments to investigate and compare the interactions of CaMWT and CaME105A mutant protein with two synthetic peptides that correspond to the two aforementioned human RyR2 regions, which we have proposed to contribute to the RyR2 CaM-binding pocket. Our data reveal that the E105A mutation has a significant negative effect on the interaction of CaM with both RyR2 regions in the presence and absence of Ca<sup>2+</sup>, highlighting the potential contribution of these two human RyR2 regions to an RyR2 CaM-binding pocket, which may be essential for physiological CaM/RyR2 association and thus channel regulation.</p><h2>Other Information</h2><p dir="ltr">Published in: International Journal of Molecular Sciences<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/ijms242115630" target="_blank">https://dx.doi.org/10.3390/ijms242115630</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_9a400e3f69e349a5bdb810547bb027fa |
| identifier_str_mv | 10.3390/ijms242115630 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/24921522 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Arrhythmia-Associated Calmodulin E105A Mutation Alters the Binding Affinity of CaM to a Ryanodine Receptor 2 CaM-Binding PocketAngelos Thanassoulas (2822861)Maria Theodoridou (33087)Laila Barrak (17714490)Emna Riguene (17714493)Tamader Alyaarabi (17714496)Mohamed A. Elrayess (7956179)F. Anthony Lai (17714499)Michail Nomikos (17563188)Biomedical and clinical sciencesCardiovascular medicine and haematologyMedical physiologyChemical sciencesMedicinal and biomolecular chemistrycalmodulinryanodine receptorRyR2arrhythmiascardiac disease<p dir="ltr">Calmodulin (CaM) is a small, multifunctional calcium (Ca<sup>2+</sup>)-binding sensor that binds and regulates the open probability of cardiac ryanodine receptor 2 (RyR2) at both low and high cytosolic Ca<sup>2+</sup> concentrations. Recent isothermal titration calorimetry (ITC) studies of a number of peptides that correspond to different regions of human RyR2 showed that two regions of human RyR2 (3584-3602aa and 4255-4271aa) bind with high affinity to CaM, suggesting that these two regions might contribute to a putative RyR2 intra-subunit CaM-binding pocket. Moreover, a previously characterized de novo long QT syndrome (LQTS)-associated missense CaM mutation (E105A) which was identified in a 6-year-old boy, who experienced an aborted first episode of cardiac arrest revealed that this mutation dysregulates normal cardiac function in zebrafish by a complex mechanism that involves alterations in both CaM-Ca<sup>2+</sup> and CaM-RyR2 interactions. Herein, to gain further insight into how the CaM E105A mutation leads to severe cardiac arrhythmia, we generated large quantities of recombinant CaMWT and CaME105A proteins. We then performed ITC experiments to investigate and compare the interactions of CaMWT and CaME105A mutant protein with two synthetic peptides that correspond to the two aforementioned human RyR2 regions, which we have proposed to contribute to the RyR2 CaM-binding pocket. Our data reveal that the E105A mutation has a significant negative effect on the interaction of CaM with both RyR2 regions in the presence and absence of Ca<sup>2+</sup>, highlighting the potential contribution of these two human RyR2 regions to an RyR2 CaM-binding pocket, which may be essential for physiological CaM/RyR2 association and thus channel regulation.</p><h2>Other Information</h2><p dir="ltr">Published in: International Journal of Molecular Sciences<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/ijms242115630" target="_blank">https://dx.doi.org/10.3390/ijms242115630</a></p>2023-10-26T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.3390/ijms242115630https://figshare.com/articles/journal_contribution/Arrhythmia-Associated_Calmodulin_E105A_Mutation_Alters_the_Binding_Affinity_of_CaM_to_a_Ryanodine_Receptor_2_CaM-Binding_Pocket/24921522CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/249215222023-10-26T03:00:00Z |
| spellingShingle | Arrhythmia-Associated Calmodulin E105A Mutation Alters the Binding Affinity of CaM to a Ryanodine Receptor 2 CaM-Binding Pocket Angelos Thanassoulas (2822861) Biomedical and clinical sciences Cardiovascular medicine and haematology Medical physiology Chemical sciences Medicinal and biomolecular chemistry calmodulin ryanodine receptor RyR2 arrhythmias cardiac disease |
| status_str | publishedVersion |
| title | Arrhythmia-Associated Calmodulin E105A Mutation Alters the Binding Affinity of CaM to a Ryanodine Receptor 2 CaM-Binding Pocket |
| title_full | Arrhythmia-Associated Calmodulin E105A Mutation Alters the Binding Affinity of CaM to a Ryanodine Receptor 2 CaM-Binding Pocket |
| title_fullStr | Arrhythmia-Associated Calmodulin E105A Mutation Alters the Binding Affinity of CaM to a Ryanodine Receptor 2 CaM-Binding Pocket |
| title_full_unstemmed | Arrhythmia-Associated Calmodulin E105A Mutation Alters the Binding Affinity of CaM to a Ryanodine Receptor 2 CaM-Binding Pocket |
| title_short | Arrhythmia-Associated Calmodulin E105A Mutation Alters the Binding Affinity of CaM to a Ryanodine Receptor 2 CaM-Binding Pocket |
| title_sort | Arrhythmia-Associated Calmodulin E105A Mutation Alters the Binding Affinity of CaM to a Ryanodine Receptor 2 CaM-Binding Pocket |
| topic | Biomedical and clinical sciences Cardiovascular medicine and haematology Medical physiology Chemical sciences Medicinal and biomolecular chemistry calmodulin ryanodine receptor RyR2 arrhythmias cardiac disease |