Intrinsic disorder within AKAP79 fine-tunes anchored phosphatase activity toward substrates and drug sensitivity

eLife

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[1] Department of Biochemistry, University of Washington, Seattle, United States;Department of Genome Sciences, University of Washington, Seattle, United States;Department of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, United States;Department of Pharmacology, University of California, San Diego, San Diego, United States;National High Magnetic Field Laboratory, Florida State University, Tallahassee, United States;

关键词: anchoring proteins;    AKAP79;    calcineurin/PP2B;    calcium signaling;    intrinsic disorder;    short linear motifs;   

DOI  :  10.7554/eLife.30872

来源: publisher

【 摘 要 】

10.7554/eLife.30872.001Scaffolding the calcium/calmodulin-dependent phosphatase 2B (PP2B, calcineurin) focuses and insulates termination of local second messenger responses. Conformational flexibility in regions of intrinsic disorder within A-kinase anchoring protein 79 (AKAP79) delineates PP2B access to phosphoproteins. Structural analysis by negative-stain electron microscopy (EM) reveals an ensemble of dormant AKAP79-PP2B configurations varying in particle length from 160 to 240 Å. A short-linear interaction motif between residues 337–343 of AKAP79 is the sole PP2B-anchoring determinant sustaining these diverse topologies. Activation with Ca2+/calmodulin engages additional interactive surfaces and condenses these conformational variants into a uniform population with mean length 178 ± 17 Å. This includes a Leu-Lys-Ile-Pro sequence (residues 125–128 of AKAP79) that occupies a binding pocket on PP2B utilized by the immunosuppressive drug cyclosporin. Live-cell imaging with fluorescent activity-sensors infers that this region fine-tunes calcium responsiveness and drug sensitivity of the anchored phosphatase.

【 授权许可】

CC BY