Structural highlights
Publication Abstract from PubMedProtein 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. The structures of protein kinase A in complex with CFTR: Mechanisms of phosphorylation and noncatalytic activation.,Fiedorczuk K, Iordanov I, Mihalyi C, Szollosi A, Csanady L, Chen J Proc Natl Acad Sci U S A. 2024 Nov 12;121(46):e2409049121. doi: , 10.1073/pnas.2409049121. Epub 2024 Nov 4. PMID:39495916[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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