Accession: | |
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Functional site class: | Calcineurin (PP2B)-docking motif PxIxI |
Functional site description: | Calcineurin (PP2B) is a Ca2+- and calmodulin-regulated serine/threonine protein phosphatase known to affect cell biological function mainly in yeast and mammalian systems but is found in all Eukaryotes. It regulates a number of different pathways, including activation of the NFAT family of transcription factors, regulation of axonal guidance, the Ca2+-dependent migration of neutrophils, synaptic plasticity, and apoptosis. The effectiveness of dephosphorylation depends not only on the proximal position of calcineurin-binding site to the dephosphorylation site but also on the flexibility of the calcineurin active site. Calcineurin has been shown to interact with two distinct linear motifs: one docking motif (DOC_PP2B_PxIxI_1) that directly interacts with the catalytic subunit A (CNA) of calcineurin, and a second docking motif (DOC_PP2B_LxvP_1) that binds to both CNA and calcineurin B (CNB), the regulatory Ca2+-binding subunit of calcineurin. |
ELMs with same tags: |
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ELM Description: | The calcineurin binding motif P.(I).(IV) is necessary for targeting and the subsequent dephosphorylation of calcineurin substrates. The calcineurin docking site is distinct from the dephosphorylation sites (which lack strong sequence conservation). The motif developed here encompasses yeast and vertebrate instances. It is likely that the motif can still be improved once more substrates are identified. |
Pattern: | .P[^P]I[^P][IV][^P] |
Pattern Probability: | 0.0001368 |
Present in taxon: | Eukaryota |
Interaction Domain: |
Metallophos (PF00149)
Calcineurin-like phosphoesterase
(Stochiometry: 1 : 1)
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The Ca2+-dependent phosphatase calcineurin, also known as protein phosphatase 2B (PP2B), is involved in a number of diverse signaling pathways in cells of different tissues. However, dephosphorylation by calcineurin is not used as broadly in cell regulation as the PP1 phosphatase. Calcineurin is evolutionarily conserved across Eukaryotes and seems to be ubiquitously expressed (Rusnak,2000). It participates in signal transduction pathways governing the development and function of the immune, nervous, cardiovascular and musculoskeletal systems (Aramburu,2004). The best-studied cellular function of calcineurin involves the regulation of T cell gene expression via dephosphorylation of NFAT family transcription factors, enabling NFAT nuclear translocation (reported in complex with calcineurin) and activation of interleukin IL-2. In yeast, the localization of PP2B substrates is dispersed, with examples of PP2B substrates present in the nucleus (Stathopoulos-Gerontides,1999), on the cytosolic side of the plasma membrane (Bultynck,2006) and cytosolic tail-anchored proteins of the endoplasmic reticulum (Heath,2004). The function of PP2B substrates in yeast is associated with various environmental stimuli that are stressful to the cell (unstressed PP2B-minus cells are viable in the laboratory) (Boustany,2002). Survival responses include correct organization of the actin cytoskeleton. Calcineurin is a heterodimeric protein consisting of calcineurin A (CNA), the catalytic subunit, and calcineurin B (CNB), the Ca2+-binding subunit. In addition to the phosphatase domain, the CNA subunit contains three regulatory domains including a CNB-binding domain, a calmodulin-binding domain, and an auto-inhibitory domain. The auto-inhibitory domain can bind to the substrate-binding pocket of the catalytic subunit, resulting in basal auto-inhibition. The CNB subunit contains four Ca2+-binding EF-hand motifs. Binding of Ca2+/calmodulin to the enzyme results in a conformational change that averts auto-inhibition and leads to activation of the phosphatase (Rusnak,2000). Activated calcineurin then dephosphorylates target S/T phosphorylation sites. Calcineurin does not necessarily dephosphorylate all sites on the substrate. Most of the residues dephosphorylated by calcineurin are in SP or TP sites, possibly explaining the associated proline isomerase. Calcineurin signaling can be effectively blocked by cyclosporin A and tacrolimus (FK506), which form a complex with a specific immunophilin binding protein (the proline isomerases cyclophilin or FKBP, respectively). Stable drug-immunophilin complexes can then block nuclear translocation of NFATs, thereby suppressing T cell activation (Lai,1998). These immunosuppressant drugs find use after organ transplantations and, in the case of tacrolimus, for ectopic treatment in atopic dermatitis. There are two independent calcineurin-binding regions called CNBR1 (DOC_PP2B_PxIxI_1) and 2 (DOC_PP2B_LxvP_1), both first reported in the N-terminal domain of NFAT. The secondary contact site LxvP contributes to the overall affinity of a substrate to calcineurin in addition to the primary PxIxI site. Recently it has been shown that both docking motifs in NFAT proteins cooperate and are required for the phosphatase activity of calcineurin (Rodriguez,2009). |



(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, Name | Start | End | Subsequence | Logic | #Ev. | Organism | Notes |
---|---|---|---|---|---|---|---|
O77638 NFATC1 NFAC1_PIG |
109 | 115 | GAPALESPRIEITSYLGLHH | TP | 3 | Sus scrofa (Pig) | |
Q65142 5EL Q65142_ASF |
204 | 210 | HRWFKKKPKIIITGCKNNVY | TP | 5 | African swine fever virus | |
O36972 Mal-047 VF238_ASFM2 |
205 | 211 | HRRFKKKPKIIITGCEDNVY | TP | 4 | African swine fever virus Malawi LIL 20/1 | |
Q05193-3 DNM1 DYN1_HUMAN |
843 | 849 | VPSRPNRAPPGVPRITISDP | TP | 4 | Homo sapiens (Human) | |
Q60591 Nfatc2 NFAC2_MOUSE |
110 | 116 | AGASGPSPRIEITPSHELMQ | TP | 1 | Mus musculus (House mouse) | |
O95644 NFATC1 NFAC1_HUMAN |
117 | 123 | GAPALESPRIEITSCLGLYH | TP | 1 | Homo sapiens (Human) | |
P40485 SLM1 SLM1_YEAST |
672 | 678 | SELQDQVPNIYIQTPINDFK | TP | 3 | Saccharomyces cerevisiae (Baker"s yeast) | |
Q99332 FRT1 HPH1_YEAST |
71 | 77 | SKSSSRLPVIAVNDNPVVPR | TP | 2 | Saccharomyces cerevisiae (Baker"s yeast) | |
P53968 CRZ1 CRZ1_YEAST |
330 | 336 | THAAPVTPIISIQEFNEGHF | TP | 2 | Saccharomyces cerevisiae (Baker"s yeast) | |
Q6VV64 Kcnk18 KCNKI_MOUSE |
209 | 215 | KPVEEAIPQIVIDAGVDELL | TP | 3 | Mus musculus (House mouse) |
Please cite:
The Eukaryotic Linear Motif resource: 2022 release.
(PMID:34718738)
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement