Intrinsically disordered regions couple the ligand binding and kinase activation of Trk neurotrophin receptors
Summary: Receptor tyrosine kinases (RTKs) are key players in development and several diseases. Understanding the molecular mechanism of RTK activation by its ligand could lead to the design of new RTK inhibitors. How the extracellular domain is coupled to the intracellular kinase domain is a matter...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222006198 |
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| author | Erik F. Kot María L. Franco Ekaterina V. Vasilieva Alexandra V. Shabalkina Alexander S. Arseniev Sergey A. Goncharuk Konstantin S. Mineev Marçal Vilar |
| author_facet | Erik F. Kot María L. Franco Ekaterina V. Vasilieva Alexandra V. Shabalkina Alexander S. Arseniev Sergey A. Goncharuk Konstantin S. Mineev Marçal Vilar |
| author_sort | Erik F. Kot |
| collection | DOAJ |
| description | Summary: Receptor tyrosine kinases (RTKs) are key players in development and several diseases. Understanding the molecular mechanism of RTK activation by its ligand could lead to the design of new RTK inhibitors. How the extracellular domain is coupled to the intracellular kinase domain is a matter of debate. Ligand-induced dimerization and ligand-induced conformational change of pre-formed dimers are two of the most proposed models. Recently we proposed that TrkA, the RTK for nerve growth factor (NGF), is activated by rotation of the transmembrane domain (TMD) pre-formed dimers upon NGF binding. However, one of the unsolved issues is how the ligand binding is conformationally coupled to the TMD rotation if unstructured extracellular juxtamembrane (eJTM) regions separate them. Here we use nuclear magnetic resonance in bicelles and functional studies to demonstrate that eJTM regions from the Trk family are intrinsically disordered and couple the ligand-binding domains and TMDs possibly via the interaction with NGF. |
| first_indexed | 2024-04-12T11:49:37Z |
| format | Article |
| id | doaj.art-9b52a2d299164968b90fdd885a5b98ad |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-12T11:49:37Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-9b52a2d299164968b90fdd885a5b98ad2022-12-22T03:34:14ZengElsevieriScience2589-00422022-06-01256104348Intrinsically disordered regions couple the ligand binding and kinase activation of Trk neurotrophin receptorsErik F. Kot0María L. Franco1Ekaterina V. Vasilieva2Alexandra V. Shabalkina3Alexander S. Arseniev4Sergey A. Goncharuk5Konstantin S. Mineev6Marçal Vilar7Moscow Institute of Physics and Technology, 141707 Dolgoprudnyi, Russian FederationMolecular Basis of Neurodegeneration Unit, Institute of Biomedicine of València (IBV-CSIC), C/ Jaume Roig 11, 46010 València, SpainShemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russian FederationShemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russian Federation; Moscow Institute of Physics and Technology, 141707 Dolgoprudnyi, Russian FederationShemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russian Federation; Moscow Institute of Physics and Technology, 141707 Dolgoprudnyi, Russian Federation; Corresponding authorShemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russian Federation; Moscow Institute of Physics and Technology, 141707 Dolgoprudnyi, Russian Federation; Corresponding authorShemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russian Federation; Moscow Institute of Physics and Technology, 141707 Dolgoprudnyi, Russian Federation; Corresponding authorMolecular Basis of Neurodegeneration Unit, Institute of Biomedicine of València (IBV-CSIC), C/ Jaume Roig 11, 46010 València, Spain; Corresponding authorSummary: Receptor tyrosine kinases (RTKs) are key players in development and several diseases. Understanding the molecular mechanism of RTK activation by its ligand could lead to the design of new RTK inhibitors. How the extracellular domain is coupled to the intracellular kinase domain is a matter of debate. Ligand-induced dimerization and ligand-induced conformational change of pre-formed dimers are two of the most proposed models. Recently we proposed that TrkA, the RTK for nerve growth factor (NGF), is activated by rotation of the transmembrane domain (TMD) pre-formed dimers upon NGF binding. However, one of the unsolved issues is how the ligand binding is conformationally coupled to the TMD rotation if unstructured extracellular juxtamembrane (eJTM) regions separate them. Here we use nuclear magnetic resonance in bicelles and functional studies to demonstrate that eJTM regions from the Trk family are intrinsically disordered and couple the ligand-binding domains and TMDs possibly via the interaction with NGF.http://www.sciencedirect.com/science/article/pii/S2589004222006198Molecular biologyStructural biologyThree-dimensional reconstruction of biomoleculair structures |
| spellingShingle | Erik F. Kot María L. Franco Ekaterina V. Vasilieva Alexandra V. Shabalkina Alexander S. Arseniev Sergey A. Goncharuk Konstantin S. Mineev Marçal Vilar Intrinsically disordered regions couple the ligand binding and kinase activation of Trk neurotrophin receptors iScience Molecular biology Structural biology Three-dimensional reconstruction of biomoleculair structures |
| title | Intrinsically disordered regions couple the ligand binding and kinase activation of Trk neurotrophin receptors |
| title_full | Intrinsically disordered regions couple the ligand binding and kinase activation of Trk neurotrophin receptors |
| title_fullStr | Intrinsically disordered regions couple the ligand binding and kinase activation of Trk neurotrophin receptors |
| title_full_unstemmed | Intrinsically disordered regions couple the ligand binding and kinase activation of Trk neurotrophin receptors |
| title_short | Intrinsically disordered regions couple the ligand binding and kinase activation of Trk neurotrophin receptors |
| title_sort | intrinsically disordered regions couple the ligand binding and kinase activation of trk neurotrophin receptors |
| topic | Molecular biology Structural biology Three-dimensional reconstruction of biomoleculair structures |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222006198 |
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