Phosphoinositide phospholipase C

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Phosphatidylinositol-specific phospholipase C
SCOP2		1gym / SCOPe / SUPFAM
OPM superfamily	118
OPM protein	1djx
CDD	cd00137
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

phosphoinositide phospholipase C
ExPASy		NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

Phosphoinositide phospholipase C (PLC, EC 3.1.4.11, triphosphoinositide phosphodiesterase, phosphoinositidase C, 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase, monophosphatidylinositol phosphodiesterase, phosphatidylinositol phospholipase C, PI-PLC, 1-phosphatidyl-D-myo-inositol-4,5-bisphosphate inositoltrisphosphohydrolase; systematic name 1-phosphatidyl-1D-myo-inositol-4,5-bisphosphate inositoltrisphosphohydrolase) is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes.

.

Phospholipase Cs participate in

.

Reaction and catalytic mechanism

All family members are capable of catalyzing the hydrolysis of PIP₂, a

(DAG).

The chemical reaction may be expressed as:

1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + H₂O ${\displaystyle \rightleftharpoons }$
1D-myo-inositol 1,4,5-trisphosphate + diacylglycerol

PLCs catalyze the reaction in two sequential steps. The first reaction is a

Cell location

Phosphoinositide phospholipase C performs its catalytic function at the

of the cell. At present, it is unclear exactly what the definitive roles for these enzymes in these cellular compartments are, particularly the nucleus.

Function

Phospholipase C performs a catalytic mechanism, depleting PIP2 and generating inositol trisphosphate (IP₃) and diacylglycerol (DAG).

Depletion of PIP2 inactivates numerous effector molecules in the plasma membrane, most notably PIP2 dependent channels and transporters responsible for setting the cell's membrane potential.^[5]

The hydrolytic products also go on to modulate the activity of downstream proteins important for cellular signaling. IP3 is soluble, and diffuses through the cytoplasm and interacts with IP3 receptors on the endoplasmic reticulum, causing the release of calcium and raising the level of intracellular calcium.

Further reading:

DAG remains within the inner leaflet of the plasma membrane due to its hydrophobic character, where it recruits protein kinase C (PKC), which becomes activated in conjunction with binding calcium ions. This results in a host of cellular responses through stimulation of calcium-sensitive proteins such as Calmodulin.

Further reading:

PI-PLC-Y
SCOP2		1qas / SCOPe / SUPFAM
OPM superfamily	126
OPM protein	2ptd
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Domain structure

In terms of domain organization, all family members possess homologous X and Y catalytic domains in the form of a distorted Triose Phosphate Isomerase (TIM) barrel with a highly disordered, charged, and flexible intervening linker region. Likewise, all isoforms possess four EF hand domains, and a single C2 domain that flank the X and Y catalytic core. An N-terminal PH domain is present in every family except for the sperm-specific ζ isoform.

Associating) domains. The β subfamily is distinguished from the others by the presence of a long C-terminal extension immediately downstream of the C2 domain, which is required for activation by G_αq subunits, and which plays a role in plasma membrane binding and nuclear localization.

Isoenzymes and activation

The phospholipase C family consists of 13 isoenzymes split between six subfamilies, PLC-δ (1,3 & 4), -β(1-4), -γ(

activity has been reported. In addition, members of the Ras superfamily of small GTPases (namely the Ras and Rho subfamilies) have also been implicated. It should also be mentioned that all forms of phospholipase C require calcium for activation, many of them possessing multiple calcium contact sites in the catalytic region. The only isoform that is known to be inactive at basal intracellular calcium levels is the δ subfamily of enzymes suggesting that they function as calcium amplifiers that become activated downstream of other PLC family members.

PLC-β

PLC-β(1-4) (120-155kDa) are activated by G_αq subunits through their C2 domain and long C-terminal extension. Gβγ subunits are known to activate the β2 and β3 isozymes only; however, this occurs through the PH domain and/or through interactions with the catalytic domain. The exact mechanism still requires further investigation. The PH domain of β2 and β3 plays a dual role, much like PLC-δ1, by binding to the plasma membrane, as well as being a site of interaction for the catalytic activator. However, PLC-β binds to the lipid surface independent of PIP₂ with all isozymes preferring phosphoinositol-3-phosphate or neutral membranes.

Members of the Rho GTPase family (e.g., Rac1, Rac2, Rac3, and

. A crystal structure of Rac1 bound to the PH domain of PLCβ2 has been solved. Like PLC-δ1, many PLC-β isoforms (in particular, PLC-β1) have been found to take up residence in the nuclear compartment. A basic amino acid region within the enzyme's long C-terminal tail appears to function as a Nuclear Localization Signal for import into the nucleus. PLC-β1 seems to play unspecified roles in cellular proliferation and differentiation.

PLC-γ

PLC-γ (120-155kDa) is activated by receptor and non-receptor

PLC-γ2

PLC-γ2 plays a major role in

In B cell signaling,

PLC-δ

The PLC-δ subfamily consists of three family members, δ1, 2, and 3. PLC-δ1 (85kDa) is the most well understood of the three. The enzyme is activated by high calcium levels generated by other PLC family members, and therefore functions as a calcium amplifier within the cell. Binding of its substrate PIP₂ to the N-terminal

PH domain

is highly specific and functions to promote activation of the catalytic core. In addition, this specificity helps tether the enzyme tightly to the plasma membrane in order to access substrate through ionic interactions between the phosphate groups of PIP2 and charged residues in the PH domain. While the catalytic core does possess a weak affinity for PIP₂, the C2 domain has been shown to mediate calcium-dependent phospholipid binding as well. In this model, the PH and C2 domains operate in concert as a "tether and fix" apparatus necessary for processive catalysis by the enzyme.

PLC-δ1 also possesses a classical

within its linker region. These two elements combined allow PLC-δ1 to actively translocate into and out of the nucleus. However, its function in the nucleus remains unclear.

The widely expressed PLC-δ1 isoform is the best-characterized phospholipase family member, as it was the first to have high-resolution

has yielded the molecular structure of the N-terminal PH domain complexed with its product IP3, as well as the remainder of the enzyme with the PH domain ablated. These structures have provided researchers with the necessary information to begin speculating about other family members such as PLCβ2.

Other PLC families

• PLC-ε (230-260kDa ) is activated by
  Ras and Rho
  GTPases.
• PLC-ζ (75kDa) is thought to play an important role in vertebrate
  fertilization by producing intracellular calcium oscillations important for the start of embryonic development. However, the mechanism of activation still remains unclear. This isoform is also capable of entering the early-formed pronucleus
  after fertilization, which seems to coincide with the cessation of calcium mobilization. It, like PLC-δ1 and PLC-β, possesses nuclear export and localization sequences.
• PLC-η has been implicated in neuronal functioning.

Human proteins in this family

PLCB1; PLCB2; PLCB3; PLCB4; PLCD1; PLCD3; PLCD4; PLCE1; PLCG1; PLCG2; PLCH1; PLCH2; PLCL1; PLCL2; PLCZ1

See also

• Clostridium perfringens alpha toxin
• Lipid signaling
• PH domain
  , found in some phospholipases C
• Phospholipase
• Zinc-dependent phospholipase C, a different family of phospholipase C

References

• Downes CP, Michell RH (1981). "The polyphosphoinositide phosphodiesterase of erythrocyte membranes". Biochem. J. 198 (1): 133–40.
  PMID 6275838
  .
• Thompson W; Dawson RMC (1964). "The triphosphoinositide phosphodiesterase of brain tissue". Biochem. J. 91 (2): 237–243.
  PMID 4284484
  .
• Rhee SG, Bae YS (1997). "Regulation of phosphoinositide-specific phospholipase C isozymes". J. Biol. Chem. 272 (24): 15045–8.
  PMID 9182519
  .
• Phospholipase+C at the U.S. National Library of Medicine Medical Subject Headings (MeSH)