Summary: Phosphatidylinositol-specific phospholipase C, X domain
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Phosphoinositide phospholipase C Edit Wikipedia article
|Phosphatidylinositol-specific phospholipase C|
|phosphoinositide phospholipase C|
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
||This article needs additional citations for verification. (July 2011)|
Phosphoinositide phospholipase C (PLC) (EC 220.127.116.11, 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) is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. These enzymes belong to a larger superfamily of Phospholipase C. Other families of phospholipase C enzymes have been identified in bacteria and trypanosomes. Phospholipases C are phosphodiesterases.
Phospholipase Cs participate in phosphatidylinositol 4,5-bisphosphate (PIP2) metabolism and lipid signaling pathways in a calcium-dependent manner. At present, the family consists of six sub-families comprising a total of 13 separate isoforms that differ in their mode of activation, expression levels, catalytic regulation, cellular localization, membrane binding avidity and tissue distribution. All are capable of catalyzing the hydrolysis of PIP2 into two important second messenger molecules, which go on to alter cell responses such as proliferation, differentiation, apoptosis, cytoskeleton remodeling, vesicular trafficking, ion channel conductance, endocrine function and neurotransmission.
Reaction and catalytic mechanism
All family members are capable of catalyzing the hydrolysis of PIP2, a phosphatidylinositol at the inner leaflet of the plasma membrane into the two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG).
The chemical reaction may be expressed as:
- 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + H2O 1D-myo-inositol 1,4,5-trisphosphate + diacylglycerol
Thus, the two substrates of this enzyme are H2O and 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate (PIP2, phosphatidylinositol bisphosphate), whereas its two products are diacylglycerol and 1D-myo-inositol 1,4,5-trisphosphate (IP3, inositol triphosphate).
PLCs catalyze the reaction in two sequential steps. The first reaction is a phosphotransferase step that involves an intramolecular attack between the hydroxyl group at the 2' position on the inositol ring and the adjacent phosphate group resulting in a cyclic IP3 intermediate. At this point, DAG is generated. However, in the second phosphodiesterase step, the cyclic intermediate is held within the active site long enough to be attacked by a molecule of water, resulting in a final acyclic IP3 product. It should be mentioned that bacterial forms of the enzyme, which contain only the catalytic lipase domain, produce cyclic intermediates exclusively, whereas the mammalian isoforms generate predominantly the acyclic product. However, it is possible to alter experimental conditions (e.g., temperature, pH) in vitro such that some mammalian isoforms will alter the degree to which they produce mixtures of cyclic/acyclic products along with DAG. This catalytic process is tightly regulated by reversible phosphorylation of different phosphoinositides and their affinity for different regulatory proteins.
PLCs perform their catalytic function at the plasma membrane where their substrate PIP2 is present. This membrane docking is mediated mostly by lipid-binding domains (e.g. PH domain and C2 domain) that display affinity for different phospholipid components of the plasma membrane. It is important to note that research has also discovered that, in addition to the plasma membrane, PLCs also exist within other sub-cellular regions such as the cytoplasm and nucleus of the cell. At present, it is unclear exactly what the definitive roles for these enzymes in these cellular compartments are, particularly the nucleus.
These molecules then 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: Function of calcium in humans
DAG remains tethered to 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: Function of protein kinase C
activated rac1 bound to its effector phospholipase c beta 2
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 Î¶ isoform.
SH2 (phosphotyrosine binding) and SH3 (proline-rich-binding) domains are found only in the Î³ form (specifically within the linker region), and only the Îµ form contains both guanine nucleotide exchange factor (GEF) and RA (Ras Associating) domains. The Î² 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 GÎ±q subunits, and which plays a role in plasma membrane binding and nuclear localization.
Isozymes and activation
The Phospholipase C family consists of 13 isozymes split between six subfamilies, PLC-Î´ (1,3 & 4), -Î²(1-4), -Î³(1,2), -Îµ, -Î¶, and the recently discovered -Î·(1,2) isoform. Depending on the specific subfamily in question, activation can be highly variable. Activation by either GÎ±q or GÎ²Î³ G-protein subunits (making it part of a G protein-coupled receptor signal transduction pathway) or by transmembrane receptors with intrinsic or associated tyrosine kinase 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 Î´ subfamily of enzymes suggesting that they function as calcium amplifiers that become activated downstream of other PLC family members.
PLC-Î²(1-4) (120-155kDa) are activated by GÎ±q subunits through their C2 domain and long C-terminal extension. GÎ²Î³ subunits are known to activate the Î²2 and Î²3 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 Î²2 and Î²3 plays a dual role, much like PLC-Î´1, by binding to the plasma membrane, as well as being a site of interaction for the catalytic activator. However, PLC-Î² 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 cdc42) have been implicated in their activation by binding to an alternate site on the N-terminal PH domain followed by subsequent recruitment to the plasma membrane. A crystal structure of Rac1 bound to the PH domain of PLCÎ²2 has been solved. The crystal structure of Like PLC-Î´1, many PLC-Î² isoforms (in particular, PLC-Î²1) 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-Î²1 seems to play unspecified roles in cellular proliferation and differentiation.
PLC-Î³ (120-155kDa) is activated by receptor and non-receptor tyrosine kinases due to the presence of two SH2 and a single SH3 domain situated betwixt a split PH domain within the linker region. Although this particular isoform does not contain classic nuclear export or localization sequences, it has been found within the nucleus of certain cell lines. There are two main isoforms of PLCÎ³ expressed in human specimens, PLC-Î³1 and PLC-Î³2.
PLC-Î³2 plays a major role in BCR signal transduction. Absence of this enzyme in knockout specimens severely inhibits the development of B cells because the same signaling pathways necessary for antigen mediated B cell activation are necessary for B cell development from CLPs.
In B cell signaling, PI 3-kinase is recruited to the BCR early in the signal transduction pathway. PI-3K phosphorylates PIP2 (Phosphatidylinositol 4,5-bisphosphate) into PIP3 (Phosphatidylinositol 3,4,5-trisphosphate). The increase in concentration of PIP3 recruits PLC-Î³2 to the BCR complex which binds to BLNK on the BCR scaffold and membrane PIP3. PLC-Î³2 is then phosphorylated by Syk on one site and Btk on two sites. PLC-Î³2 then competes with PI-3K for PIP2 which it hydrolyzes into IP3 (inositol 1,4,5-triphosphate), which ultimately raises intercellular calcium, and diacylglycerol (DAG), which activates portions of the PKC family. Because PLC-Î³2 competes for PIP2 with the original signaling molecule PI3K, it serves as a negative feedback mechanism.
The PLC-Î´ subfamily consists of three family members, Î´1, 2, and 3. PLC-Î´1 (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-Î´1 also possesses a classical leucine-rich nuclear export signal (NES) in its EF hand motif, as well as a Nuclear localization signal within its linker region. These two elements combined allow PLC-Î´1 to actively translocate into and out of the nucleus. However, its function in the nucleus remains unclear.
The widely expressed PLC-Î´1 isoform is the best-characterized phospholipase family member, as it was the first to have high-resolution X-ray crystal structures available for analysis. In terms of domain architecture, all of the enzymes are built upon a common PLC-Î´ backbone, wherein each family displays similarities, as well as obvious distinctions, that contribute to unique regulatory properties within the cell. Because it is the only family found expressed in lower eukaryotic organisms such as yeast and slime molds, it is considered the prototypical PLC isoform. The other family members more than likely evolved from PLC-Î´ as their domain architecture and mechanism of activation were expanded. Although a full crystal structure has not been obtained, high-resolution X-ray crystallography 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 PLCÎ²2.
Other PLC families
- PLC-Îµ (230-260kDa ) is activated by Ras and Rho GTPases.
- PLC-Î¶ (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-Î´1 and PLC-Î², possesses nuclear export and localization sequences.
- PLC-Î· has been implicated in neuronal functioning.
Human proteins in this family
- Meldrum E, Parker PJ, Carozzi A (1991). "The PtdIns-PLC superfamily and signal transduction". Biochim. Biophys. Acta 1092 (1): 49â71. doi:10.1016/0167-4889(91)90177-Y. PMID 1849017.
- Rhee SG, Choi KD (1992). "Multiple forms of phospholipase C isozymes and their activation mechanisms". Adv. Second Messenger Phosphoprotein Res. 26: 35â61. PMID 1419362.
- Rhee SG, Choi KD (1992). "Regulation of inositol phospholipid-specific phospholipase C isozymes". J. Biol. Chem. 267 (18): 12393â12396. PMID 1319994.
- Sternweis PC, Smrcka AV (1992). "Regulation of phospholipase C by G proteins". Trends Biochem. Sci. 17 (12): 502â506. doi:10.1016/0968-0004(92)90340-F. PMID 1335185.
- DeFranco, Anthony (2008). "Chapter 8: B Lymphocyte Signaling Mechanisms and Activation". In Paul, William. Fundamental Immunology (Book
|url=(help)) (6th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 270â288. ISBN 0-7817-6519-6.
- Downes CP, Michell RH (1981). "The polyphosphoinositide phosphodiesterase of erythrocyte membranes". Biochem. J. 198 (1): 133â40. PMC 1163219. PMID 6275838.
- Thompson W and Dawson RMC (1964). "The triphosphoinositide phosphodiesterase of brain tissue". Biochem. J. 91 (2): 237â243. PMC 1202878. PMID 4284484.
- Rhee SG, Bae YS (1997). "Regulation of phosphoinositide-specific phospholipase C isozymes". J. Biol. Chem. 272 (24): 15045â8. doi:10.1074/jbc.272.24.15045. PMID 9182519.
- Clostridium perfringens alpha toxin
- Lipid signaling
- Zinc-dependent phospholipase C, a different family of phospholipase C
- PH domain, found in some phospholipases C
- Phospholipase C at the US National Library of Medicine Medical Subject Headings (MeSH)
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Phosphatidylinositol-specific phospholipase C, X domain Provide feedback
This associates with PF00387 to form a single structural unit.
Internal database links
|Similarity to PfamA using HHSearch:||GDPD|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000909Phosphatidylinositol-specific phospholipase C (EC), a eukaryotic intracellular enzyme, plays an important role in signal transduction processes [PUBMED:1849017]. It catalyzes the hydrolysis of 1-phosphatidyl-D-myo-inositol-3,4,5-triphosphate into the second messenger molecules diacylglycerol and inositol-1,4,5-triphosphate. This catalytic process is tightly regulated by reversible phosphorylation and binding of regulatory proteins [PUBMED:1419362, PUBMED:1319994, PUBMED:1335185]. In mammals, there are at least 6 different isoforms of PI-PLC, they differ in their domain structure, their regulation, and their tissue distribution. Lower eukaryotes also possess multiple isoforms of PI-PLC. All eukaryotic PI-PLCs contain two regions of homology, sometimes referred to as the 'X-box' and 'Y-box'. The order of these two regions is always the same (NH2-X-Y-COOH), but the spacing is variable. In most isoforms, the distance between these two regions is only 50-100 residues but in the gamma isoforms one PH domain, two SH2 domains, and one SH3 domain are inserted between the two PLC-specific domains. The two conserved regions have been shown to be important for the catalytic activity. By profile analysis, we could show that sequences with significant similarity to the X-box domain occur also in prokaryotic and trypanosome PI-specific phospholipases C. Apart from this region, the prokaryotic enzymes show no similarity to their eukaryotic counterparts.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||phospholipase C activity (GO:0004629)|
|Biological process||intracellular signal transduction (GO:0035556)|
|lipid metabolic process (GO:0006629)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Number in seed:||140|
|Number in full:||2890|
|Average length of the domain:||145.10 aa|
|Average identity of full alignment:||30 %|
|Average coverage of the sequence by the domain:||19.62 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||14|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
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Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 4 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the PI-PLC-X domain has been found. There are 50 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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