TY - JOUR TI - Intrinsic disorder within AKAP79 fine-tunes anchored phosphatase activity toward substrates and drug sensitivity AU - Nygren, Patrick J AU - Mehta, Sohum AU - Schweppe, Devin K AU - Langeberg, Lorene K AU - Whiting, Jennifer L AU - Weisbrod, Chad R AU - Bruce, James E AU - Zhang, Jin AU - Veesler, David AU - Scott, John D A2 - Davis, Roger J VL - 6 PY - 2017 DA - 2017/10/02 SP - e30872 C1 - eLife 2017;6:e30872 DO - 10.7554/eLife.30872 UR - https://doi.org/10.7554/eLife.30872 AB - Scaffolding 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. KW - anchoring proteins KW - AKAP79 KW - calcineurin/PP2B KW - calcium signaling KW - intrinsic disorder KW - short linear motifs JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -