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Sci. STKE, 22 May 2001
Vol. 2001, Issue 83, p. tw1
[DOI: 10.1126/stke.2001.83.tw1]


Protein Motifs Zipping in the Regulators

Marx et al. show that the leucine/isoleucine zipper (LZ) protein motif found in several ion channels appears to mediate interaction of the channels with key regulatory proteins. They characterized the role of LZ motifs in ryanodine receptors (RyRs), which are ligand-controlled ion channels essential for proper excitation-contraction coupling in muscle. The activity of RyRs is regulated by phosphorylation, which modulates the channel properties of these receptors, and increased phosphorylation of RyR2 (the cardiac form of RyRs) is associated with heart failure. RyR2 has three LZ domains, each of which interacted with a distinct cellular regulator: LZ1 conferred binding of protein phosphatase 1 (PP1) through interaction with the PP1-targeting protein spinophilin, LZ2 conferred binding of PP2A through the PP2A-targeting protein PR130, and LZ3 mediated binding of the cyclic AMP-dependent protein kinase through the targeting protein mAKAP (also known as A-kinase anchoring protein). Each of the three targeting proteins also has LZ domains, which are required for specific interactions with LZ domains of RyR2. Disruption of the LZ-mediated interactions by incubation of receptor complexes with fusion proteins containing the LZ domains of RyR2 resulted in changes in RyR channel activity and altered regulation by phosphorylation. The identification of LZ-mediated interactions enabled Marks et al. to predict kinase and phosphatase interactions with RyR1 and, thus, may facilitate identification of components in other channel complexes and, thus, may expose other potential targets for therapeutic intervention.

S. O. Marx, S. Reiken, Y. Hisamatsu, M. Gaburjakova, J. Gaburjakova, Y.-M. Yang, N. Rosemblit, A. R. Marks, Phosphorylation-dependent regulation of ryanodine receptors: A novel role for leucine/isoleucine zippers. J. Cell Biol. 153, 699-708 (2001). [Abstract] [Full Text]

Citation: Zipping in the Regulators. Sci. STKE 2001, tw1 (2001).

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