Calcineurin acts on a select group of protein substrates by recognizing two SLiMs, PxIxIT and LxVP, which occur in disordered, accessible, protein regions, but may be hundreds of residues away from sites of dephophosphorylation and are found at variable distances and orientations with respect to each other. PxIxIT and LxVP sequences were first defined in the NFAT (nuclear factor of activated T-cells) family of transcription factors, whose nuclear accumulation is triggered by calcineurin-mediated dephosphorylation to initiate gene expression and promote T-cell activation. Subsequently, PxIxIT and LxVP motifs were identified in multiple calcineurin substrates from humans and budding yeast (S. cerevisiae), and their binding surfaces on calcineurin shown to be broadly conserved, suggesting that this characteristic mode of substrate recognition is retained throughout the fungal and animal kingdoms.
Filter: PxIxIT & LxVP | PxIxIT | LxVP | Predicted
References
(1) "Association of protein kinase A and protein phosphatase 2B with a common anchoring protein." Coghlan VM, Perrino BA, Howard M, Langeberg LK, Hicks JB, Gallatin WM, Scott JD. Science. 1995 Jan;267 (5194):108-11
(2) "AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region." Kashishian A, Howard M, Loh C, Gallatin WM, Hoekstra MF, Lai Y. J. Biol. Chem.. 1998 Oct;273 (42):27412-9
(3) "Balanced interactions of calcineurin with AKAP79 regulate Ca2+-calcineurin-NFAT signaling." Li H, Pink MD, Murphy JG, Stein A, Dell'Acqua ML, Hogan PG. Nat. Struct. Mol. Biol.. 2012 Feb;19 (3):337-45
(4) "A calcineurin-dependent switch controls the trafficking function of α-arrestin Aly1/Art6." O'Donnell AF, Huang L, Thorner J, Cyert MS. J. Biol. Chem.. 2013 Aug;288 (33):24063-80
(5) "Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes." Sun L, Youn HD, Loh C, Stolow M, He W, Liu JO. Immunity. 1998 Jun;8 (6):703-11
(6) "Deletion of calcineurin and myocyte enhancer factor 2 (MEF2) binding domain of Cabin1 results in enhanced cytokine gene expression in T cells." Esau C, Boes M, Youn HD, Tatterson L, Liu JO, Chen J. J. Exp. Med.. 2001 Nov;194 (10):1449-59
(7) "Domain architecture of the regulators of calcineurin (RCANs) and identification of a divergent RCAN in yeast." Mehta S, Li H, Hogan PG, Cunningham KW. Mol. Cell. Biol.. 2009 May;29 (10):2777-93
(8) "A conserved docking surface on calcineurin mediates interaction with substrates and immunosuppressants." Rodríguez A, Roy J, Martínez-Martínez S, López-Maderuelo MD, Niño-Moreno P, Ortí L, Pantoja-Uceda D, Pineda-Lucena A, Cyert MS, Redondo JM. Mol. Cell. 2009 Mar;33 (5):616-26
(9) "Dephosphorylation of cAMP-dependent protein kinase regulatory subunit (type II) by calmodulin-dependent protein phosphatase. Determinants of substrate specificity." Blumenthal DK, Takio K, Hansen RS, Krebs EG. J. Biol. Chem.. 1986 Jun;261 (18):8140-5
(10) "A reassessment of the inhibitory capacity of human FKBP38 on calcineurin." Weiwad M, Edlich F, Erdmann F, Jarczowski F, Kilka S, Dorn M, Pechstein A, Fischer G. FEBS Lett.. 2005 Mar;579 (7):1591-6
(11) "The calcineurin signaling network evolves via conserved kinase-phosphatase modules that transcend substrate identity." Goldman A, Roy J, Bodenmiller B, Wanka S, Landry CR, Aebersold R, Cyert MS. Mol. Cell. 2014 Aug;55 (3):422-35
(12) "Isoform-specific dephosphorylation of dynamin1 by calcineurin couples neurotrophin receptor endocytosis to axonal growth." Bodmer D, Ascaño M, Kuruvilla R. Neuron. 2011 Jun;70 (6):1085-99
(13) "Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death." Cribbs JT, Strack S. EMBO Rep.. 2007 Oct;8 (10):939-44
(14) "Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria." Cereghetti GM, Stangherlin A, Martins de Brito O, Chang CR, Blackstone C, Bernardi P, Scorrano L. Proc. Natl. Acad. Sci. U.S.A.. 2008 Oct;105 (41):15803-8
(14) "Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria." Cereghetti GM, Stangherlin A, Martins de Brito O, Chang CR, Blackstone C, Bernardi P, Scorrano L. Proc. Natl. Acad. Sci. U.S.A.. 2008 Oct;105 (41):15803-8
(15) "A calcineurin docking motif (LXVP) in dynamin-related protein 1 contributes to mitochondrial fragmentation and ischemic neuronal injury." Slupe AM, Merrill RA, Flippo KH, Lobas MA, Houtman JC, Strack S. J. Biol. Chem.. 2013 Apr;288 (17):12353-65
(16) "Hcm1 integrates signals from Cdk1 and calcineurin to control cell proliferation." Arsenault HE, Roy J, Mapa CE, Cyert MS, Benanti JA. Mol. Biol. Cell. 2015 Oct;26 (20):3570-7
(17) "KSR2 is a calcineurin substrate that promotes ERK cascade activation in response to calcium signals." Dougherty MK, Ritt DA, Zhou M, Specht SI, Monson DM, Veenstra TD, Morrison DK. Mol. Cell. 2009 Jun;34 (6):652-62
(18) "The KSR2-calcineurin complex regulates STIM1-ORAI1 dynamics and store-operated calcium entry (SOCE)." Giurisato E, Gamberucci A, Ulivieri C, Marruganti S, Rossi E, Giacomello E, Randazzo D, Sorrentino V. Mol. Biol. Cell. 2014 Jun;25 (11):1769-81
(19) "Selective inhibition of NFAT activation by a peptide spanning the calcineurin targeting site of NFAT." Aramburu J, Garcia-Cózar F, Raghavan A, Okamura H, Rao A, Hogan PG. Mol. Cell. 1998 Apr;1 (5):627-37
(20) "Delineation of the intimate details of the backbone conformation of pyridine nucleotide coenzymes in aqueous solution." Bose KS, Sarma RH. Biochem. Biophys. Res. Commun.. 1975 Oct;66 (4):1173-9
(21) "Blockade of NFAT activation by the second calcineurin binding site." Martínez-Martínez S, Rodríguez A, López-Maderuelo MD, Ortega-Pérez I, Vázquez J, Redondo JM. J. Biol. Chem.. 2006 Mar;281 (10):6227-35
(22) "The calcineurin phosphatase complex modulates immunogenic B cell responses." Winslow MM, Gallo EM, Neilson JR, Crabtree GR. Immunity. 2006 Feb;24 (2):141-52
(23) "The BioPlex Network: A Systematic Exploration of the Human Interactome." Huttlin EL, Ting L, Bruckner RJ, Gebreab F, Gygi MP, Szpyt J, Tam S, Zarraga G, Colby G, Baltier K, Dong R, Guarani V, Vaites LP, Ordureau A, Rad R, Erickson BK, Wühr M, Chick J, Zhai B, Kolippakkam D, Mintseris J, Obar RA, Harris T, Artavanis-Tsakonas S, Sowa ME, De Camilli P, Paulo JA, Harper JW, Gygi SP. Cell. 2015 Jul;162 (2):425-40
(24) "Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity." Okamura H, Aramburu J, García-Rodríguez C, Viola JP, Raghavan A, Tahiliani M, Zhang X, Qin J, Hogan PG, Rao A. Mol. Cell. 2000 Sep;6 (3):539-50
(25) "Slm1 and slm2 are novel substrates of the calcineurin phosphatase required for heat stress-induced endocytosis of the yeast uracil permease." Bultynck G, Heath VL, Majeed AP, Galan JM, Haguenauer-Tsapis R, Cyert MS. Mol. Cell. Biol.. 2006 Jun;26 (12):4729-45
(26) "Calcineurin regulates the yeast synaptojanin Inp53/Sjl3 during membrane stress." Guiney EL, Goldman AR, Elias JE, Cyert MS. Mol. Biol. Cell. 2015 Feb;26 (4):769-85
(27) "Targeting of calcineurin to an NFAT-like docking site is required for the calcium-dependent activation of the background K+ channel, TRESK." Czirják G, Enyedi P. J. Biol. Chem.. 2006 May;281 (21):14677-82
(27) "Targeting of calcineurin to an NFAT-like docking site is required for the calcium-dependent activation of the background K+ channel, TRESK." Czirják G, Enyedi P. J. Biol. Chem.. 2006 May;281 (21):14677-82
(28) "TRESK background K(+) channel is inhibited by PAR-1/MARK microtubule affinity-regulating kinases in Xenopus oocytes." Braun G, Nemcsics B, Enyedi P, Czirják G. PLoS ONE. 2011 ;6 (12):e28119
(29) "The LQLP calcineurin docking site is a major determinant of the calcium-dependent activation of human TRESK background K+ channel." Czirják G, Enyedi P. J. Biol. Chem.. 2014 Oct;289 (43):29506-18
(30) "Hph1p and Hph2p, novel components of calcineurin-mediated stress responses in Saccharomyces cerevisiae." Heath VL, Shaw SL, Roy S, Cyert MS. Eukaryotic Cell. 2004 Jun;3 (3):695-704
(31) "Specific α-arrestins negatively regulate Saccharomyces cerevisiae pheromone response by down-modulating the G-protein-coupled receptor Ste2." Alvaro CG, O'Donnell AF, Prosser DC, Augustine AA, Goldman A, Brodsky JL, Cyert MS, Wendland B, Thorner J. Mol. Cell. Biol.. 2014 Jul;34 (14):2660-81
(32) "Calcineurin, the Ca" Ly N, Cyert MS. Mol. Biol. Cell. 2017 Mar;28 (5):576-586
(33) "Cooperative autoinhibition and multi-level activation mechanisms of calcineurin." Li SJ, Wang J, Ma L, Lu C, Wang J, Wu JW, Wang ZX. Cell Res.. 2016 Mar;26 (3):336-49
(34) "Splice cassette II of Na+,HCO3(-) cotransporter NBCn1 (slc4a7) interacts with calcineurin A: implications for transporter activity and intracellular pH control during rat artery contractions." Danielsen AA, Parker MD, Lee S, Boron WF, Aalkjaer C, Boedtkjer E. J. Biol. Chem.. 2013 Mar;288 (12):8146-55
(35) "Na(+)/H(+) exchanger 1 directly binds to calcineurin A and activates downstream NFAT signaling, leading to cardiomyocyte hypertrophy." Hisamitsu T, Nakamura TY, Wakabayashi S. Mol. Cell. Biol.. 2012 Aug;32 (16):3265-80
(36) "Calcineurin-dependent regulation of Crz1p nuclear export requires Msn5p and a conserved calcineurin docking site." Boustany LM, Cyert MS. Genes Dev.. 2002 Mar;16 (5):608-19
(37) "Towards a proteome-scale map of the human protein-protein interaction network." Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M. Nature. 2005 Oct;437 (7062):1173-8
(38) "Next-generation sequencing to generate interactome datasets." Yu H, Tardivo L, Tam S, Weiner E, Gebreab F, Fan C, Svrzikapa N, Hirozane-Kishikawa T, Rietman E, Yang X, Sahalie J, Salehi-Ashtiani K, Hao T, Cusick ME, Hill DE, Roth FP, Braun P, Vidal M. Nat. Methods. 2011 Jun;8 (6):478-80
(39) "A proteome-scale map of the human interactome network." Rolland T, Taşan M, Charloteaux B, Pevzner SJ, Zhong Q, Sahni N, Yi S, Lemmens I, Fontanillo C, Mosca R, Kamburov A, Ghiassian SD, Yang X, Ghamsari L, Balcha D, Begg BE, Braun P, Brehme M, Broly MP, Carvunis AR, Convery-Zupan D, Corominas R, Coulombe-Huntington J, Dann E, Dreze M, Dricot A, Fan C, Franzosa E, Gebreab F, Gutierrez BJ, Hardy MF, Jin M, Kang S, Kiros R, Lin GN, Luck K, MacWilliams A, Menche J, Murray RR, Palagi A, Poulin MM, Rambout X, Rasla J, Reichert P, Romero V, Ruyssinck E, Sahalie JM, Scholz A, Shah AA, Sharma A, Shen Y, Spirohn K, Tam S, Tejeda AO, Trigg SA, Twizere JC, Vega K, Walsh J, Cusick ME, Xia Y, Barabási AL, Iakoucheva LM, Aloy P, De Las Rivas J, Tavernier J, Calderwood MA, Hill DE, Hao T, Roth FP, Vidal M. Cell. 2014 Nov;159 (5):1212-26
(40) "Physical interaction between calcineurin and Cav3.2 T-type Ca2+ channel modulates their functions." Huang CH, Chen YC, Chen CC. FEBS Lett.. 2013 Jun;587 (12):1723-30