دورية أكاديمية
A multiscale model of mechanotransduction by the ankyrin chains of the NOMPC channel.
| العنوان: | A multiscale model of mechanotransduction by the ankyrin chains of the NOMPC channel. |
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| المؤلفون: | Argudo D; Cardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA., Capponi S; Cardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA., Bethel NP; Cardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA., Grabe M; Cardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA michael.grabe@ucsf.edu. |
| المصدر: | The Journal of general physiology [J Gen Physiol] 2019 Mar 04; Vol. 151 (3), pp. 316-327. Date of Electronic Publication: 2019 Feb 06. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Rockefeller University Press Country of Publication: United States NLM ID: 2985110R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1540-7748 (Electronic) Linking ISSN: 00221295 NLM ISO Abbreviation: J Gen Physiol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: New York, N.Y. : Rockefeller University Press Original Publication: New York, N.Y. : Rockefeller Institute for Medical Research, c1918- |
| مواضيع طبية MeSH: | Mechanotransduction, Cellular*, Ankyrins/*chemistry , Drosophila Proteins/*chemistry , Transient Receptor Potential Channels/*chemistry, Animals ; Ankyrins/metabolism ; Binding Sites ; Drosophila ; Drosophila Proteins/metabolism ; Ion Channel Gating ; Molecular Dynamics Simulation ; Protein Binding ; Transient Receptor Potential Channels/metabolism |
| مستخلص: | Our senses of touch and hearing are dependent on the conversion of external mechanical forces into electrical impulses by the opening of mechanosensitive channels in sensory cells. This remarkable feat involves the conversion of a macroscopic mechanical displacement into a subnanoscopic conformational change within the ion channel. The mechanosensitive channel NOMPC, responsible for hearing and touch in flies, is a homotetramer composed of four pore-forming transmembrane domains and four helical chains of 29 ankyrin repeats that extend 150 Å into the cytoplasm. Previous work has shown that the ankyrin chains behave as biological springs under extension and that tethering them to microtubules could be involved in the transmission of external forces to the NOMPC gate. Here we combine normal mode analysis (NMA), full-atom molecular dynamics simulations, and continuum mechanics to characterize the material properties of the chains under extreme compression and extension. NMA reveals that the lowest-frequency modes of motion correspond to fourfold symmetric compression/extension along the channel, and the lowest-frequency symmetric mode for the isolated channel domain involves rotations of the TRP domain, a putative gating element. Finite element modeling reveals that the ankyrin chains behave as a soft spring with a linear, effective spring constantof 22 pN/nm for deflections ≤15 Å. Force-balance analysis shows that the entire channel undergoes rigid body rotation during compression, and more importantly, each chain exerts a positive twisting moment on its respective linker helices and TRP domain. This torque is a model-independent consequence of the bundle geometry and would cause a clockwise rotation of the TRP domain when viewed from the cytoplasm. Force transmission to the channel for compressions >15 Å depends on the nature of helix-helix contact. Our work reveals that compression of the ankyrin chains imparts a rotational torque on the TRP domain, which potentially results in channel opening. (© 2019 Argudo et al.) |
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| معلومات مُعتمدة: | T32 EB009383 United States EB NIBIB NIH HHS; T32 HL007731 United States HL NHLBI NIH HHS |
| سلسلة جزيئية: | PDB 5VKQ |
| المشرفين على المادة: | 0 (Ankyrins) 0 (Drosophila Proteins) 0 (NOMPC protein, Drosophila) 0 (Transient Receptor Potential Channels) |
| تواريخ الأحداث: | Date Created: 20190208 Date Completed: 20200526 Latest Revision: 20231006 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC6400526 |
| DOI: | 10.1085/jgp.201812266 |
| PMID: | 30728217 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1540-7748 |
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| DOI: | 10.1085/jgp.201812266 |