Difference between revisions of "Phosphatase Family HP1"

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[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Superfamily_Histidine_Phosphatase|Histidine phosphatase superfamily]]:  [[Phosphatase_Family_Histidine_Phosphatase_Branch1|HP, branch1 family]]
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__NOTOC__
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[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_HP|Fold HP]]: [[Phosphatase_Superfamily_HP|Superfamily HP]]:  [[Phosphatase_Family_HP1|HP, branch1 family]]  
  
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Two subfamilies in this family have been reported as protein phosphatases. Refer to Pfam ID [http://pfam.xfam.org/family/PF00300 PF00300] for general information.
 
  
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======PGAM5======
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HP1 is one of two major families within the Histidine Phosphatase fold, that uses a pHis intermediate during catalysis. HP1 includes several non-protein phosphatases, and two protein phosphatase subfamilies: PGAM5 is a serine phosphatase and STS (TULA or UBASH3) is a tyrosine phosphatase.
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[http://www.ncbi.nlm.nih.gov/gene/192111 PGAM5] (phosphoglycerate mutase family member 5) is found in metazoan and many protists but is absent from fungi, plants, and amoebozoa. PGAM5 is first thought as an enzyme of intermediary metabolism that converts 3-phosphoglycerate to 2-phosphoglycerate in glycolysis. Later, Takeda ''et al.'' reported  that PGAM5 dephosphorylates and activates MAP kinase kinase kinase ASK1 <cite>PGAM5_1</cite>. PGAM5 is anchored in the mitochondrial membrane and it lacks PGAM activity, but instead it associates with ASK1 and activates ASK1 by dephosphorylation of inhibitory sites. Mutation of an active site His-105 in PGAM5 abolished phosphatase activity with ASK1 and pThr peptides as substrates. The Drosophila and ''Caenorhabditis elegans'' orthologs of PGAM5 also exhibit specific Ser/Thr phosphatase activity and activate the corresponding Drosophila and ''C. elegans'' ASK1 kinases <cite>PGAM5_1</cite>. PGAM5 was also reported to dephosphorylate the serine 637 site of Drp1. The dephosphorylation activates the GTPase activity of Drp1 and causes mitochondrial fragmentation, an early and obligatory step for necrosis execution <cite>PGAM5_2</cite>. PGAM5 was recently reported to dephosphorylate FUNDC1 at Ser-13 and thereby activates mitophagy <cite>chen14</cite>.
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======TULAs======
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=== Subfamilies found in human ===
  
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There are two TULAs in human, UBASH3A (STS-2 or TULA-1) and UBASH3B (STS-1 or TULA-2). TULA-1 is present in lobe-finned fish, birds and mammals, but not other bony fishes. TULA-2 emerged earlier than TULA-1, which is found in most metazoan, from sponge to nematodes, insects, fishes, birds, and mammals. Both TULAs negatively regulate the endocytosis of receptor tyrosine kinases. The UBA domain of TULA-1 and SH3-dependent Cbl-binding are required for this function. TULA-1 (STS-2) is a lymphoid protein, whereas TULA-2 (STS-1) is expressed ubiquitously. It has been shown that TULA-2 can dephosphorylate phospho-tyrosines on EGFR and Syk. The histidine phosphatase domain of TULA-2, but not of TULA-1, dephosphorylates the EGFR at multiple tyrosines, and thereby terminating its signalling and endocytosis <cite>STS_1</cite>. TULA-2 decreases tyrosine phosphorylation of Syk in vivo and in vitro. Inactivated TULA-2 increases tyrosine phosphorylation of Syk in cells co-transfected to overexpress these proteins, thus acting as a dominant-negative form that suppresses dephosphorylation of Syk caused by endogenous TULA-2. However, the same assay on TULA-1 shows the phosphatase activity of TULA-1 is negligible compared to TULA-2 <cite>STS_2</cite>.
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======[[Phosphatase_Subfamily_PGAM|PGAM]]======
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PGAMs mainly function as glycolytic enzymes regulating intracellular levels of their substrate [[Phosphatase_Glossary#3-phosphoglycerate|3-phosphoglycerate]] and product [[Phosphatase_Glossary#2-phosphoglycerate|2-phosphoglycerate]]. Human BPGM is a 2,3-bisphosphoglycerate mutase. They are found throughout most eukaryotes.
  
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======[[Phosphatase_Subfamily_PGAM5|PGAM5]]: serine phosphatase at inner mitochondria membrane ======
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PGAM5 is a protein serine phosphatase conserved in metazoa. It localized to inner mitochondria membrane. It has distinct substrates, such as ASK1, Drp1, FUNDC1. PGAM5 is involved in mitophagy regulation.
  
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===References===
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======[[Phosphatase_Subfamily_TIGAR|TIGAR]]: TP53 Induced Glycolysis and Apoptosis Regulatory phosphatase======
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<biblio>
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TIGAR inhibits glycolysis and negatively modulates the level of intracellular reactive oxygen species (ROS), therefore regulating autophagy and apoptosis. TIGAR is found in chordates some basal [[Phosphatase_Glossary#Eumetazoa|eumetazoa]], but is absent from nematodes and arthropods.
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#Rigden pmid=18092946
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#PGAM5_1 pmid=19590015
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======[[Phosphatase_Subfamily_STS|STS]] (TULA or UBASH3): tyrosine phosphatase ======
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#PGAM5_2 pmid=22265414
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STS is a protein tyrosine phosphatase involved in T-cell receptor signaling. In particular, STS dephosphorylates the Syk subfamily kinases Syk and ZAP-70. STS is conserved in metazoa, but ''C. elegans'' lost the signature domains, SH3 and H2 domain, which are common among STSs.
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#chen14 pmid=24746696
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#STS_1 pmid=17880946
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======[[Phosphatase_Subfamily_PFKFB|PFKFB]]======
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#STS_2 pmid=18189269
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PFKFB is a bifunctional enzyme responsible for the synthesis (as kinase) and degradation (as phosphatase) of [[Phosphatase_Glossary#Fructose-2.2C6-bisphosphatase|fructose-2,6-bisphosphate]] a glycolytic regulator.
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</biblio>
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=== Other subfamilies ===
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======[[Phosphatase_Subfamily_TFC7|TFC7]]======
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TFC7 is a RNA pol III transcription initiation factor complex (TFIIIC) subunit found in fungi and Dictyostelium.
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======[[Phosphatase_Subfamily_HP1LE|HP1LE]]======
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HP1LE  subfamily is found in choanoflagellates and sponge, but is absent from eumetazoa. Its function is unclear.

Latest revision as of 21:54, 25 October 2016

Phosphatase Classification: Fold HP: Superfamily HP: HP, branch1 family


HP1 is one of two major families within the Histidine Phosphatase fold, that uses a pHis intermediate during catalysis. HP1 includes several non-protein phosphatases, and two protein phosphatase subfamilies: PGAM5 is a serine phosphatase and STS (TULA or UBASH3) is a tyrosine phosphatase.

Subfamilies found in human

PGAM

PGAMs mainly function as glycolytic enzymes regulating intracellular levels of their substrate 3-phosphoglycerate and product 2-phosphoglycerate. Human BPGM is a 2,3-bisphosphoglycerate mutase. They are found throughout most eukaryotes.

PGAM5: serine phosphatase at inner mitochondria membrane

PGAM5 is a protein serine phosphatase conserved in metazoa. It localized to inner mitochondria membrane. It has distinct substrates, such as ASK1, Drp1, FUNDC1. PGAM5 is involved in mitophagy regulation.

TIGAR: TP53 Induced Glycolysis and Apoptosis Regulatory phosphatase

TIGAR inhibits glycolysis and negatively modulates the level of intracellular reactive oxygen species (ROS), therefore regulating autophagy and apoptosis. TIGAR is found in chordates some basal eumetazoa, but is absent from nematodes and arthropods.

STS (TULA or UBASH3): tyrosine phosphatase

STS is a protein tyrosine phosphatase involved in T-cell receptor signaling. In particular, STS dephosphorylates the Syk subfamily kinases Syk and ZAP-70. STS is conserved in metazoa, but C. elegans lost the signature domains, SH3 and H2 domain, which are common among STSs.

PFKFB

PFKFB is a bifunctional enzyme responsible for the synthesis (as kinase) and degradation (as phosphatase) of fructose-2,6-bisphosphate a glycolytic regulator.

Other subfamilies

TFC7

TFC7 is a RNA pol III transcription initiation factor complex (TFIIIC) subunit found in fungi and Dictyostelium.

HP1LE

HP1LE subfamily is found in choanoflagellates and sponge, but is absent from eumetazoa. Its function is unclear.

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