The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
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:
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)
o See 10 Instances for DOC_PP2B_PxIxI_1
o Abstract
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).
o 13 selected references:

o 14 GO-Terms:

o 10 Instances for DOC_PP2B_PxIxI_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
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
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: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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