8AHY

X-ray structure of human NCS-1 bound to Ric-8A

Summary for 8AHY

• Entry DOI: 10.2210/pdb8ahy/pdb
• Descriptor: Neuronal calcium sensor 1, Synembryn-A, CALCIUM ION, ... (9 entities in total)
• Functional Keywords: ncs-1, ric-8a, complex, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 24646.47

Authors

Munoz-Reyes, D.,Sanchez-Barrena, M.J. (deposition date: 2022-07-25, release date: 2023-12-13, Last modification date: 2024-01-10)

Primary citation

Munoz-Reyes, D.,McClelland, L.J.,Arroyo-Urea, S.,Sanchez-Yepes, S.,Sabin, J.,Perez-Suarez, S.,Menendez, M.,Mansilla, A.,Garcia-Nafria, J.,Sprang, S.,Sanchez-Barrena, M.J.
The neuronal calcium sensor NCS-1 regulates the phosphorylation state and activity of the G alpha chaperone and GEF Ric-8A.
Elife, 12:-, 2023

PubMed Abstract: The neuronal calcium sensor 1 (NCS-1), an EF-hand Ca binding protein, and Ric-8A coregulate synapse number and probability of neurotransmitter release. Recently, the structures of Ric-8A bound to Gα have revealed how Ric-8A phosphorylation promotes Gα recognition and activity as a chaperone and guanine nucleotide exchange factor. However, the molecular mechanism by which NCS-1 regulates Ric-8A activity and its interaction with Gα subunits is not well understood. Given the interest in the NCS-1/Ric-8A complex as a therapeutic target in nervous system disorders, it is necessary to shed light on this molecular mechanism of action at atomic level. We have reconstituted NCS-1/Ric-8A complexes to conduct a multimodal approach and determine the sequence of Ca signals and phosphorylation events that promote the interaction of Ric-8A with Gα. Our data show that the binding of NCS-1 and Gα to Ric-8A are mutually exclusive. Importantly, NCS-1 induces a structural rearrangement in Ric-8A that traps the protein in a conformational state that is inaccessible to casein kinase II-mediated phosphorylation, demonstrating one aspect of its negative regulation of Ric-8A-mediated G-protein signaling. Functional experiments indicate a loss of Ric-8A guanine nucleotide exchange factor (GEF) activity toward Gα when complexed with NCS-1, and restoration of nucleotide exchange activity upon increasing Ca concentration. Finally, the high-resolution crystallographic data reported here define the NCS-1/Ric-8A interface and will allow the development of therapeutic synapse function regulators with improved activity and selectivity.

PubMed: 38018500
DOI: 10.7554/eLife.86151

Experimental method

X-RAY DIFFRACTION (1.7 Å)