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Literature summary for 3.1.3.16 extracted from
- Serine/threonine phosphatases in atrial fibrillation (2017), J. Mol. Cell. Cardiol., 103, 110-120 .
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| I-1 | the regulatory subunit I-1 (PPP1R1A) is a selective and potent enzyme PP1 inhibitor that facilitates crosstalk between different protein phosphatases and kinases. Protein kinase A-dependent phosphorylation of Thr35 activates I-1. As such, PKA-dependent I-1 activation and subsequent PP1 inhibition form a positive feedback loop amplifying the phosphorylation of several substrates during beta-adrenoceptor (beta-AR) stimulation. Dephosphorylation of I-1 Thr35 is mediated by enzymes PP2A and calcineurin, thereby creating additional crosstalk between different phosphatases | Homo sapiens |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| cytoplasm | - |
Homo sapiens | 5737 | - |
| additional information | the regulatory subunits have specific subcellular localizations, for example B56epsilon (PP2R5E) and PR72/PR130 (PPP2R3A) near the Z-line, or B56gamma (PP2R5C) and PR53 (PP2R4) near the nucleus. PP2A co-localizes with connexins | Homo sapiens | - |
- |
| myofilament | among the PP1 isoforms, PP1beta appears to be preferentially targeted to the myofilaments | Homo sapiens | 36379 | - |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Ca2+ | a Ca2+-dependent phosphatase | Homo sapiens |  |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| [protein I-1]-serine/threonine phosphate + H2O | Homo sapiens | substrate is a regulatory subunit I-1 (PPP1R1A) of phosphatase PP1, dephosphorylation of I-1 at Thr35 by PP2A deactivates I-1 and thus activates enzyme PP1 | [protein I-1]-serine/threonine + phosphate | - |
? | |
| [protein]-serine/threonine phosphate + H2O | Homo sapiens | - |
[protein]-serine/threonine + phosphate | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | P62136 | catalytic subunit alpha | - |
| Homo sapiens | P67775 | catalytic subunit alpha | - |
| Homo sapiens | Q08209 | catalytic subunit alpha | - |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| atrium | - |
Homo sapiens | - |
| cardiomyocyte cell line | - |
Homo sapiens | - |
| cardiomyocyte cell line | atrial | Homo sapiens | - |
| heart | - |
Homo sapiens | - |
| additional information | PP1 is ubiquitously expressed. PP1 co-localizes with connexins | Homo sapiens | - |
| additional information | PP2A is ubiquitously expressed | Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| [protein I-1]-serine/threonine phosphate + H2O | substrate is a regulatory subunit I-1 (PPP1R1A) of phosphatase PP1, dephosphorylation of I-1 at Thr35 by PP2A deactivates I-1 and thus activates enzyme PP1 | Homo sapiens | [protein I-1]-serine/threonine + phosphate | - |
? | |
| [protein I-1]-serine/threonine phosphate + H2O | substrate is a regulatory subunit I-1 (PPP1R1A) of phosphatase PP1 | Homo sapiens | [protein I-1]-serine/threonine + phosphate | - |
? | |
| [protein]-serine/threonine phosphate + H2O | - |
Homo sapiens | [protein]-serine/threonine + phosphate | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| More | enzyme PP2A can exist as a dimer of a catalytic (PP2A-C) and scaffold (PP2A-A) subunits, or as a trimer of scaffolding, catalytic and regulatory subunits | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| calcineurin | - |
Homo sapiens |
| PP1 | - |
Homo sapiens |
| PP2A | - |
Homo sapiens |
| PP2B | - |
Homo sapiens |
| serine/threonine phosphatase | - |
Homo sapiens |
| type-1 phosphatase | - |
Homo sapiens |
| type-2A phosphatase | - |
Homo sapiens |
| type-2B phosphatase | - |
Homo sapiens |
Expression
| Organism | Comment | Expression |
|---|---|---|
| Homo sapiens | both expression and activity of calcineurin A subunit are increased in paroxysmal atrial fibrillation and chronic atrial fibrillation patients | up |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | analysis of mechanisms controlling the phosphorylation of these proteins and focus on the role of altered dephosphorylation via local type-1, type-2A and type-2B phosphatases (PP1, PP2A, and PP2B, also known as calcineurin, respectively) | Homo sapiens |
| evolution | analysis of mechanisms controlling the phosphorylation of these proteins and focus on the role of altered dephosphorylation via local type-1, type-2A and type-2B phosphatases (PP1, PP2A, and PP2B, also known as calcineurin, respectively). Three different CnA isoforms (CnAalpha/PPP3CA, CnAbeta/PPP3CB, and CnAgamma/PPP3CC) have been identified, of which CnAalpha and CnAbeta are ubiquitously expressed. CnB is expressed by two genes (CnBalpha/PPP3R1 and CnBbeta/PPP3R2) | Homo sapiens |
| malfunction | dysfunction of the regulation of cardiac proteins by serine/threonine protein phosphatases can contribute to the initiation, maintenance and progression of cardiac arrhythmias. Atrial fibrillation (AF) is the most common heart rhythm disorder and is characterized by electrical, autonomic, calcium-handling, contractile, and structural remodeling, which include, among other things, changes in the phosphorylation status of a wide range of proteins. AF-associated alterations in the phosphorylation of atrial ion channels, calcium-handling and contractile proteins, and their role in atrial fibrillation-pathophysiology, overview. AF significantly affects morbidity and mortality as a risk factor for worsening heart failure and stroke. The regulatory subunit I-1 (PPP1R1A) is a selective and potent enzyme PP1 inhibitor that facilitates crosstalk between different protein phosphatases and kinases. Protein kinase A-dependent phosphorylation of Thr35 activates I-1. As such, PKA-dependent I-1 activation and subsequent PP1 inhibition form a positive feedback loop amplifying the phosphorylation of several substrates during beta-adrenoceptor (beta-AR) stimulation. The regulatory subunit I-1 (PPP1R1A) of phosphatase PP1 is dephosphorylated at Thr35 by phosphatase PP2A deactivating I-1 and thus activating enzyme PP1. PKCalpha phosphorylates I-1 on Ser67, decreasing I-1 activity and substrate phosphorylation, but Ser67 phosphorylation levels are unchanged in AF patients. AF-related changes in I-1-mediated regulation (inhibition) of PP1 are unlikely to explain the increase in global PP1 activity. Altered regulation of cardiac electrophysiology and contraction by protein phosphatases in AF, AF-related modulation of Ca2+-handling by protein phosphatases, overview. Increased phosphatase activity in heart failure decreases gap-junction coupling through multiple mechanisms. Loss of PP1beta increases phosphorylation of myosin light chain 2 and cMyBP-C | Homo sapiens |
| malfunction | dysfunction of the regulation of cardiac proteins by serine/threonine protein phosphatases can contribute to the initiation, maintenance and progression of cardiac arrhythmias. Atrial fibrillation (AF) is the most common heart rhythm disorder and is characterized by electrical, autonomic, calcium-handling, contractile, and structural remodeling, which include, among other things, changes in the phosphorylation status of a wide range of proteins. Atrial fibrillation-associated alterations in the phosphorylation of atrial ion channels, calcium-handling and contractile proteins, and their role in atrial fibrillation-pathophysiology, overview. Atrial fibrillation significantly affects morbidity and mortality as a risk factor for worsening heart failure and stroke. Altered regulation of cardiac electrophysiology and contraction by protein phosphatases in AF, AF-related modulation of Ca2+-handling by protein phosphatases, overview. Increased phosphatase activity in heart failure decreases gap-junction coupling through multiple mechanisms | Homo sapiens |
| malfunction | dysfunction of the regulation of cardiac proteins by serine/threonine protein phosphatases can contribute to the initiation, maintenance and progression of cardiac arrhythmias. Atrial fibrillation (AF) is the most common heart rhythm disorder and is characterized by electrical, autonomic, calcium-handling, contractile, and structural remodeling, which include, among other things, changes in the phosphorylation status of a wide range of proteins. Atrial fibrillation-associated alterations in the phosphorylation of atrial ion channels, calcium-handling and contractile proteins, and their role in atrial fibrillation-pathophysiology, overview. Atrial fibrillation significantly affects morbidity and mortality as a risk factor for worsening heart failure and stroke. Both expression and activity of calcineurin A subunit are increased in paroxysmal atrial fibrillation and chronic atrial fibrillation patients. Altered regulation of cardiac electrophysiology and contraction by protein phosphatases in AF, AF-related modulation of Ca2+-handling by protein phosphatases, overview | Homo sapiens |
| physiological function | calcineurin (PP2B) is a Ca2+-dependent phosphatase consisting of catalytic (CnA) and regulatory (CnB) subunits that link Ca2+- and phosphorylation-dependent signaling pathways. Serine/threonine protein phosphatases control dephosphorylation of numerous cardiac proteins, including a variety of ion channels and calcium-handling proteins, thereby providing precise post-translational regulation of cardiac electrophysiology and function | Homo sapiens |
| physiological function | serine/threonine protein phosphatases control dephosphorylation of numerous cardiac proteins, including a variety of ion channels and calcium-handling proteins, thereby providing precise post-translational regulation of cardiac electrophysiology and function. Dephosphorylation of I-1, the regulatory subunit I-1 (PPP1R1A) of phosphatase PP1, by PP2A deactivates I-1 and thus activates enzyme PP1. PP2A-A (PPP2R1) expression is unchanged in cAF patients, but the expression of PP2A-C (PPP2C) is increased, potentially explaining the increased enzymatic activity. By contrast, PP2A-C expression is unchanged in pAF patients. Functional regulation by PP2A is spatially-heterogeneous. Regulatory subunits may also play a critical inhibitory role in the regulation of PP2A activity in the heart. For example, B56alpha (PPP2R5A) overexpression decreases phosphatase activity and increases RyR2 phosphorylation, whereas loss of B56alpha results in PP2A-mediated RyR2 dephosphorylation. Atrial contractility is also regulated by phosphorylation of contractile proteins, including the inhibitory troponin subunit (TnI), which influences Ca2+-sensitivity of the myofilaments and cMyBP-C, which determines Ca2+-sensitivity and kinetics of cross-bridge cycling. PP1 and PP2A are the major phosphatases controlling dephosphorylation of myofilament proteins. PP1 preferentially dephosphorylates Ser23/24 on TnI, whereas PP2A induces a more uniform dephosphorylation | Homo sapiens |
| physiological function | serine/threonine protein phosphatases control dephosphorylation of numerous cardiac proteins, including a variety of ion channels and calcium-handling proteins, thereby providing precise post-translational regulation of cardiac electrophysiology and function. The PP2A-catalytic subunit can bind directly to the poreforming L-type Ca2+-channel alpha1C-subunit, in close proximity to the PKA phosphorylation site Ser1928, but this interaction can be further modulated by multiple regulatory subunits and other phosphatases. Disruption of PP2A binding using inhibitory peptides increase the L-type Ca2+-current, suggesting an important inhibitory role for channel-bound PP2A. PP1 and PP2A are the major phosphatases controlling dephosphorylation of myofilament proteins. PP1 preferentially dephosphorylates Ser23/24 on TnI, whereas PP2A induces a more uniform dephosphorylation | Homo sapiens |
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