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Fig. 7. Model for the amino acid interactions that regulate UNC-43 localization. A schematic model for UNC-43 regulatory amino acid interactions between the catalytic domain (the gray box) and the autoinhibitory domain (the black line and gray cylinder). Electrostatic interactions between amino acid side chains are indicated by a dotted line. Hydrophobic pockets created within the catalytic domain are indicated by the white ovals. A hypothetical factor that transports UNC-43 to the neurites is indicated by the white cylinder. Negatively-charged side chains are indicated by black circles, whereas positively-charged side chains are indicated by white circles. The black star in B indicates the addition of a phosphate at T286. (A) In the absence of activity, UNC-43 is kept quiescent by amino acid interactions between the catalytic domain and the autoinhibitory domain. (B) Upon calcium activation, calmodulin (not shown) binds and displaces the autoinhibitory domain, allowing for autophosphorylation at T286. The residues K148 and D238 are made available to bind to outside factors that facilitate the translocation of UNC-43 to neurites. (C) The T286D mutation mimics phosphorylation, even in the absence of calcium stimulation, by introducing charge at T286, displacing the autoinhibitory domain from the hydrophobic pocket along the catalytic domain. This constitutively exposes K148 and D238 for binding to outside factors, resulting in the over-transport of UNC-43 to the neurites. (D) The D238R mutation destabilizes an electrostatic interaction required for the autoinhibitory domain to bind to the catalytic domain, thereby resulting in constitutive kinase activity. The mutation also destabilizes a separate electrostatic interaction required for the catalytic domain to interact with the transport factors that facilitate UNC-43 localization to the neurites.
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