التفاصيل البيبلوغرافية
| العنوان: |
Disordered Domain Shifts the Conformational Ensemble of the Folded Regulatory Domain of the Multidomain Oncoprotein c-Src. |
| المؤلفون: |
Gurumoorthy V; UT/ORNL Graduate School of Genome and Science Technology, University of Tennessee, Knoxville, Tennessee 37996, United States., Shrestha UR; UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States., Zhang Q; Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States., Pingali SV; Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States., Boder ET; Department of Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, Tennessee 37996, United States., Urban VS; Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States., Smith JC; UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States., Petridis L; UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States., O'Neill H; Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States. |
| المصدر: |
Biomacromolecules [Biomacromolecules] 2023 Feb 13; Vol. 24 (2), pp. 714-723. Date of Electronic Publication: 2023 Jan 24. |
| نوع المنشور: |
Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: |
English |
| بيانات الدورية: |
Publisher: American Chemical Society Country of Publication: United States NLM ID: 100892849 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1526-4602 (Electronic) Linking ISSN: 15257797 NLM ISO Abbreviation: Biomacromolecules Subsets: MEDLINE |
| أسماء مطبوعة: |
Original Publication: Washington, DC : American Chemical Society, c2000- |
| مواضيع طبية MeSH: |
Molecular Dynamics Simulation* , Proto-Oncogene Proteins pp60(c-src)*, Catalytic Domain ; Protein Domains |
| مستخلص: |
c-Src kinase is a multidomain non-receptor tyrosine kinase that aberrantly phosphorylates several signaling proteins in cancers. Although the structural properties of the regulatory domains (SH3-SH2) and the catalytic kinase domain have been extensively characterized, there is less knowledge about the N-terminal disordered region (SH4UD) and its interactions with the other c-Src domains. Here, we used domain-selective isotopic labeling combined with the small-angle neutron scattering contrast matching technique to study SH4UD interactions with SH3-SH2. Our results show that in the presence of SH4UD, the radius of gyration ( R g ) of SH3-SH2 increases, indicating that it has a more extended conformation. Hamiltonian replica exchange molecular dynamics simulations provide a detailed molecular description of the structural changes in SH4UD-SH3-SH2 and show that the regulatory loops of SH3 undergo significant conformational changes in the presence of SH4UD, while SH2 remains largely unchanged. Overall, this study highlights how a disordered region can drive a folded region of a multidomain protein to become flexible, which may be important for allosteric interactions with binding partners. This may help in the design of therapeutic interventions that target the regulatory domains of this important family of kinases. |
| المشرفين على المادة: |
EC 2.7.10.2 (Proto-Oncogene Proteins pp60(c-src)) |
| تواريخ الأحداث: |
Date Created: 20230124 Date Completed: 20230222 Latest Revision: 20230309 |
| رمز التحديث: |
20240829 |
| DOI: |
10.1021/acs.biomac.2c01158 |
| PMID: |
36692364 |
| قاعدة البيانات: |
MEDLINE |
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