cd16217

EF-hand motif found in phosphoinositide phospholipase C delta 1 (PI-PLC-delta1)

CDD entry
Member databaseCDD
CDD typedomain
Short nameEFh_PI-PLCdelta1
SetEFh_PI-PLC

Description

PI-PLC-delta1, also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 (PLCD1), or phospholipase C-III (PLC-III), or phospholipase C-delta-1 (PLC-delta-1), is present in high abundancy in the brain, heart, lung, skeletal muscle and testis. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. PI-PLC-delta1 is required for maintenance of homeostasis in skin and metabolic tissues. Moreover, it is essential in trophoblasts for placental development. Simultaneous loss of PI-PLC-delta1 may cause placental vascular defects, leading to embryonic lethality. PI-PLC-delta1 can be positively or negatively regulated by several binding partners, including p122/Rho GTPase activating protein (RhoGAP), Gha/Transglutaminase II, RalA, and calmodulin. It is involved in Alzheimer's disease and hypertension. Furthermore, PI-PLC-delta1 regulates cell proliferation and cell-cycle progression from G1- to S-phase by control of cyclin E-CDK2 activity and p27 levels. It can be activated by alpha1-adrenoreceptors (AR) in a calcium-dependent manner and may be important for G protein-coupled receptors (GPCR) responses in vascular smooth muscle (VSM). PI-PLC-delta1 may also be involved in noradrenaline (NA)-induced phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis and modulate sustained contraction of mesenteric small arteries. In addition, it inhibits thermogenesis and induces lipid accumulation, and therefore contributes to the development of obesity. PI-PLC-delta1 contains a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C-terminal C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. PI-PLC-delta1 can regulate the binding of PH domain to PIP2 in a Ca2+-dependent manner through its functionally important EF-hand domains. In addition, PI-PLC-delta1 possesses a classical leucine-rich nuclear export sequence (NES) located in the EF hand motifs, as well as a nuclear localization signal within its linker region, both of which may be responsible for translocating PI-PLC-delta1 into and out of the cell nucleus.
[8, 11, 2, 12, 3, 6, 7, 9, 4, 5, 10, 1]

References

1.Membrane targeting of C2 domains of phospholipase C-delta isoforms. Ananthanarayanan B, Das S, Rhee SG, Murray D, Cho W. J Biol Chem 277, 3568-75, (2002). PMID: 11706040

2.A ternary metal binding site in the C2 domain of phosphoinositide-specific phospholipase C-delta1. Essen LO, Perisic O, Lynch DE, Katan M, Williams RL. Biochemistry 36, 2753-62, (1997). View articlePMID: 9062102

3.C2 domain conformational changes in phospholipase C-delta 1. Grobler JA, Essen LO, Williams RL, Hurley JH. Nat. Struct. Biol. 3, 788-95, (1996). View articlePMID: 8784353

4.Phosphorylation of phospholipase C-delta 1 regulates its enzymatic activity. Fujii M, Yi KS, Kim MJ, Ha SH, Ryu SH, Suh PG, Yagisawa H. J Cell Biochem 108, 638-50, (2009). PMID: 19681039

5.Phospholipase C delta 1 regulates cell proliferation and cell-cycle progression from G1- to S-phase by control of cyclin E-CDK2 activity. Kaproth-Joslin KA, Li X, Reks SE, Kelley GG. Biochem J 415, 439-48, (2008). PMID: 18588506

6.Functional analysis of duplicated genes and N-terminal splice variant of phospholipase C-δ1 in Paralichthys olivaceus. Kim NY, Kim MS, Ahn SJ, Seo JS, Bak HJ, Kim BS, Jo HI, Jang HY, Jo HS, Lee HH, Chung JK. Comp Biochem Physiol B Biochem Mol Biol 165, 201-10, (2013). PMID: 23629421

7.Nonmuscle myosin IIA (myosin heavy polypeptide 9): a novel class of signal transducer mediating the activation of G alpha h/phospholipase C-delta 1 pathway. Lin YF, Yeh TS, Chen SF, Tsai YH, Chou CM, Yang YY, Huang HM. Endocrinology 151, 876-85, (2010). PMID: 20068007

8.Deletion and site-directed mutagenesis of EF-hand domain of phospholipase C-delta 1: effects on its activity. Nakashima S, Banno Y, Watanabe T, Nakamura Y, Mizutani T, Sakai H, Zhao Y, Sugimoto Y, Nozawa Y. Biochem Biophys Res Commun 211, 365-9, (1995). PMID: 7794245

9.The small GTPase Ral couples the angiotensin II type 1 receptor to the activation of phospholipase C-delta 1. Godin CM, Ferreira LT, Dale LB, Gros R, Cregan SP, Ferguson SS. Mol Pharmacol 77, 388-95, (2010). PMID: 20018811

10.Phospholipase C-delta1 modulates sustained contraction of rat mesenteric small arteries in response to noradrenaline, but not endothelin-1. Clarke CJ, Forman S, Pritchett J, Ohanian V, Ohanian J. Am J Physiol Heart Circ Physiol 295, H826-34, (2008). PMID: 18567701

11.Crystal structure of a mammalian phosphoinositide-specific phospholipase C delta. Essen LO, Perisic O, Cheung R, Katan M, Williams RL. Nature 380, 595-602, (1996). View articlePMID: 8602259

12.Expression, characterization, and crystallization of the catalytic core of rat phosphatidylinositide-specific phospholipase C delta 1. Grobler JA, Hurley JH. Protein Sci 5, 680-6, (1996). PMID: 8845757

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