9DW7

Dephosphorylated CFTR in 1:2 complex with PKA-C

Summary for 9DW7

• Entry DOI: 10.2210/pdb9dw7/pdb
• EMDB information: 47237
• Descriptor: cAMP-dependent protein kinase catalytic subunit alpha, Cystic fibrosis transmembrane conductance regulator, cystic fibrosis transmembrane conductance regulator, ... (5 entities in total)
• Functional Keywords: cftr, pka, complex, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 251880.57

Authors

Fiedorczuk, K.,Chen, J.,Csanady, L. (deposition date: 2024-10-08, release date: 2024-11-13, Last modification date: 2025-05-14)

Primary citation

Fiedorczuk, K.,Iordanov, I.,Mihalyi, C.,Szollosi, A.,Csanady, L.,Chen, J.
The structures of protein kinase A in complex with CFTR: Mechanisms of phosphorylation and noncatalytic activation.
Proc.Natl.Acad.Sci.USA, 121:e2409049121-e2409049121, 2024

PubMed Abstract: Protein kinase A (PKA) is a key regulator of cellular functions by selectively phosphorylating numerous substrates, including ion channels, enzymes, and transcription factors. It has long served as a model system for understanding the eukaryotic kinases. Using cryoelectron microscopy, we present complex structures of the PKA catalytic subunit (PKA-C) bound to a full-length protein substrate, the cystic fibrosis transmembrane conductance regulator (CFTR)-an ion channel vital to human health. CFTR gating requires phosphorylation of its regulatory (R) domain. Unphosphorylated CFTR engages PKA-C at two locations, establishing two "catalytic stations" near to, but not directly involving, the R domain. This configuration, coupled with the conformational flexibility of the R domain, permits transient interactions of the eleven spatially separated phosphorylation sites. Furthermore, we determined two structures of the open-pore CFTR stabilized by PKA-C, providing a molecular basis to understand how PKA-C stimulates CFTR currents even in the absence of phosphorylation.

PubMed: 39495916
DOI: 10.1073/pnas.2409049121

Experimental method

ELECTRON MICROSCOPY (6 Å)