Research ArticleStructural Biology

A Computational Model Predicts That Gβγ Acts at a Cleft Between Channel Subunits to Activate GIRK1 Channels

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Science Signaling  13 Aug 2013:
Vol. 6, Issue 288, pp. ra69
DOI: 10.1126/scisignal.2004075

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Mechanism of Gβγ Activation of a GIRK Channel

G protein (heterotrimeric guanine nucleotide–binding protein)–regulated inwardly rectifying K+ (GIRK) channels are critically involved in functions such as regulation of heart rate and control of neuronal excitability and are regulated by G protein βγ subunits (Gβγ). Mahajan et al. pursued a multistage computational docking approach to predict the site of interaction between the GIRK1 channel’s cytosolic domain and Gβγ. Follow-up on the predicted interacting residues in proteins expressed in Xenopus oocytes confirmed the model and indicated that Gβγ stabilized the open conformation of an intersubunit cleft in the channel. Analysis of Gβγ activation of GIRK4 homomeric channels did not show the same dependence on opening the intersubunit cleft, but activation of heteromeric GIRK1/GIRK4 channels did. Thus, multistage computational docking model predictions supported by experimental results offer a powerful approach for investigating the interactions between components of protein complexes.

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