Academic Journal
A neurodevelopmental disorder mutation locks G proteins in the transitory pre-activated state
| العنوان: | A neurodevelopmental disorder mutation locks G proteins in the transitory pre-activated state |
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| المؤلفون: | Kevin M. Knight, Brian E. Krumm, Nicholas J. Kapolka, W. Grant Ludlam, Meng Cui, Sepehr Mani, Iya Prytkova, Elizabeth G. Obarow, Tyler J. Lefevre, Wenyuan Wei, Ning Ma, Xi-Ping Huang, Jonathan F. Fay, Nagarajan Vaidehi, Alan V. Smrcka, Paul A. Slesinger, Diomedes E. Logothetis, Kirill A. Martemyanov, Bryan L. Roth, Henrik G. Dohlman |
| المصدر: | Nature Communications, Vol 15, Iss 1, Pp 1-18 (2024) |
| بيانات النشر: | Nature Portfolio |
| سنة النشر: | 2024 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | Science |
| الوصف: | Many neurotransmitter receptors activate G proteins through exchange of GDP for GTP. The intermediate nucleotide-free state has eluded characterization, due largely to its inherent instability. Here we characterize a G protein variant associated with a rare neurological disorder in humans. Gαo K46E has a charge reversal that clashes with the phosphate groups of GDP and GTP. As anticipated, the purified protein binds poorly to guanine nucleotides yet retains wild-type affinity for G protein βγ subunits. In cells with physiological concentrations of nucleotide, Gαo K46E forms a stable complex with receptors and Gβγ, impeding effector activation. Further, we demonstrate that the mutant can be easily purified in complex with dopamine-bound D2 receptors, and use cryo-electron microscopy to determine the structure, including both domains of Gαo, without nucleotide or stabilizing nanobodies. These findings reveal the molecular basis for the first committed step of G protein activation, establish a mechanistic basis for a neurological disorder, provide a simplified strategy to determine receptor-G protein structures, and a method to detect high affinity agonist binding in cells. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2041-1723 |
| Relation: | https://doi.org/10.1038/s41467-024-50964-z; https://doaj.org/toc/2041-1723; https://doaj.org/article/a1bbb4b8f5a447f79e49586a70a5bd73 |
| DOI: | 10.1038/s41467-024-50964-z |
| الاتاحة: | https://doi.org/10.1038/s41467-024-50964-z https://doaj.org/article/a1bbb4b8f5a447f79e49586a70a5bd73 |
| رقم الانضمام: | edsbas.13B2C493 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 20411723 |
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| DOI: | 10.1038/s41467-024-50964-z |