دورية أكاديمية
Multiple proteolytic events in caspase-6 self-activation impact conformations of discrete structural regions.
| العنوان: | Multiple proteolytic events in caspase-6 self-activation impact conformations of discrete structural regions. |
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| المؤلفون: | Dagbay KB; Department of Chemistry, University of Massachusetts, Amherst, MA 01002., Hardy JA; Department of Chemistry, University of Massachusetts, Amherst, MA 01002 hardy@chem.umass.edu. |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Sep 19; Vol. 114 (38), pp. E7977-E7986. Date of Electronic Publication: 2017 Sep 01. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | Molecular Dynamics Simulation* , Proteolysis*, Caspase 6/*chemistry, Caspase 6/metabolism ; Deuterium Exchange Measurement ; Humans ; Protein Domains ; Protein Structure, Secondary |
| مستخلص: | Caspase-6 is critical to the neurodegenerative pathways of Alzheimer's, Huntington's, and Parkinson's diseases and has been identified as a potential molecular target for treatment of neurodegeneration. Thus, understanding the global and regional changes in dynamics and conformation provides insights into the unique properties of caspase-6 that may contribute to achieving control of its function. In this work, hydrogen/deuterium exchange MS (H/DX-MS) was used to map the local changes in the conformational flexibility of procaspase-6 at the discrete states that reflect the series of cleavage events that ultimately lead to the fully active, substrate-bound state. Intramolecular self-cleavage at Asp-193 evoked higher solvent exposure in the regions of the substrate-binding loops L1, L3, and L4 and in the 130s region, the intersubunit linker region, the 26-32 region as well as in the stabilized loop 2. Additional removal of the linker allowed caspase-6 to gain more flexibility in the 130s region and in the L2 region converting caspase-6 to a competent substrate-binding state. The prodomain region was found to be intrinsically disordered independent of the activation state of caspase-6; however, its complete removal resulted in the protection of the adjacent 26-32 region, suggesting that this region may play a regulatory role. The molecular details of caspase-6 dynamics in solution provide a comprehensive scaffold for strategic design of therapeutic approaches for neurodegenerative disorders. Competing Interests: The authors declare no conflict of interest. |
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| معلومات مُعتمدة: | R01 GM080532 United States GM NIGMS NIH HHS |
| فهرسة مساهمة: | Keywords: apoptosis; conformational dynamics; cysteine protease; hydrogen exchange MS; neurodegeneration |
| المشرفين على المادة: | EC 3.4.22.- (CASP6 protein, human) EC 3.4.22.- (Caspase 6) |
| تواريخ الأحداث: | Date Created: 20170903 Date Completed: 20180605 Latest Revision: 20181113 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC5617271 |
| DOI: | 10.1073/pnas.1704640114 |
| PMID: | 28864531 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1091-6490 |
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| DOI: | 10.1073/pnas.1704640114 |