Protein phosphatase 1
Encyclopedia
Phosphoprotein phosphatase 1 (PP1) belongs to a certain class of phosphatases known as protein serine
/ threonine
phosphatases. This type of phosphatase includes metal-dependent protein phosphatases (PPMs) and aspartate-based phosphatases. PP1 has been found to be important in the control of glycogen
metabolism, muscle contraction
, cell progression, neuronal activities, splicing of RNA
, mitosis
, cell division, apoptosis
, protein synthesis, and regulation of membrane receptors and channels.
. Some common regulatory subunits include GM and GL, which are named after their locations of action within the body (Muscle and Liver respectively).
X-ray crystallographic structural data is available for PP1 catalytic subunit. The catalytic subunit of PP1 forms an α/β fold with a central β-sandwich arranged between two α-helical domains. The interaction of the three β-sheets of the β-sandwich creates a channel for catalytic activity, as it is the site of coordination of metal ions. These metal ions have been identified as Mn and Fe and their coordination is provided by three histidines, two aspartic acids, and one asparagine.
Potential inhibitors include a variety of naturally occurring toxins including okadaic acid, a diarrhetic shelfish poison, strong tumor promoter, and microcystin
. Microcystin is a liver toxin produced by blue-green algae and contains a cyclic heptapeptide structure that that interacts with three distinct regions of the surface of the catalytic subunit of PP1. The structure of MCLR does not change when compexed with PP1, but the catalytic subunit of PP1 does in order to avoid steric effectsof Tyr 276 of PP1 and Mdha side chain of MCLR.
Phosphorylase a serves a glucose sensor in liver cells. When glucose levels are low, phosphorylase a in its active R state has PP1 bound tightly. This binding to phosphorylase a prevents any phosphatase activity of PP1 and maintains the active phosphorylated configuration. Therefore, there phosphorylase a will accelerate glycogen breakdown until adequate levels of glucose are achieved. When glucose concentrations get too high, phosphorylase a is converted to its inactive, T state. By shifting phosphorylase a to its T state, PP1 dissociates from the complex. This dissociation activates glycogen synthase and converts phosphorylase a to phosphorylase b. It should be noted that phosphorylase b does not bind PP1 allowing PP1 to remain activated.
When the muscles of the body signal for the need for glycogen degradation and increased glucose concentration, PP1 will be regulated accordingly. Protein kinase A can reduce the activity of PP1. The glycogen binding region, GM becomes phosporylated which causes its dissociation from the catalytic PP1 unit. This separation of the catalytic PP1 unit, glycogen, and other substrates causes a significant decrease in dephosphorylation. Also, when other substrates become phosphorylated by protein kinase A, they can bind to the catalytic subunit of PP1 and directly inhibit it. In the end, phophorylase is kept its active form and glycogen synthase in its inactive form.
-associated protein inhibits the assembly of microtubules in neurons. Researchers at the New York State Institute for Basic Research in Developmental Disabilities showed that there is significantly lower type 1 phosphatase activity in both gray and white matters in Alzheimer disease brains. This suggests that phosphatases play a key role in the onset of Alzheimer's.
Regulation of HIV
-1 transcription
by Protein Phosphatase 1 (PP1). It has been recognized that protein phosphatase-1 (PP1) serves as an important regulator of HIV-1 transcription. Researchers at Howard University showed that Tat
protein targets PP1 to the nucleus and the consequent interact is important for HIV-1 transcription.
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
/ threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
phosphatases. This type of phosphatase includes metal-dependent protein phosphatases (PPMs) and aspartate-based phosphatases. PP1 has been found to be important in the control of glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
metabolism, muscle contraction
Muscle contraction
Muscle fiber generates tension through the action of actin and myosin cross-bridge cycling. While under tension, the muscle may lengthen, shorten, or remain the same...
, cell progression, neuronal activities, splicing of RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
, mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
, cell division, apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, protein synthesis, and regulation of membrane receptors and channels.
Enzyme Structure
Each PP1 enzyme contains both a catalytic subunit and a regulatory subunit. The catalytic subunit consists of a 30-kD single-domain protein that can form complexes with other regulatory subunits. The catalytic subunit is highly conserved among all eukaryotes, thus suggesting a common catalytic mechanism. The catalytic subunit can from complexes with various regulatory subunits. These regulatory subunits play an important role in substrate specificity as well as compartmentalizationCompartmentalization
Compartmentalization or compartmentalisation may refer to:* Compartmentalization * Compartmentalization * Compartmentalization * Compartmentalization...
. Some common regulatory subunits include GM and GL, which are named after their locations of action within the body (Muscle and Liver respectively).
X-ray crystallographic structural data is available for PP1 catalytic subunit. The catalytic subunit of PP1 forms an α/β fold with a central β-sandwich arranged between two α-helical domains. The interaction of the three β-sheets of the β-sandwich creates a channel for catalytic activity, as it is the site of coordination of metal ions. These metal ions have been identified as Mn and Fe and their coordination is provided by three histidines, two aspartic acids, and one asparagine.
Enzyme Mechanism
The mechanism involves two metal ions binding and activating water, which initiates a nucleophilic attack on the phosphorus atom.Regulation
Regulation of these different processes is performed by distinct PP1 holoenzymes that facilitate the complexation of the PP1 catalytic subunit to various regulatory subunits.Potential inhibitors include a variety of naturally occurring toxins including okadaic acid, a diarrhetic shelfish poison, strong tumor promoter, and microcystin
Microcystin
Microcystins are cyclic nonribosomal peptides produced by cyanobacteria . They are cyanotoxins and can be very toxic for plants and animals including humans. Their hepatotoxicity may cause serious damage to the liver. Microcystins can strongly inhibit protein phosphatases type 1 and 2A , and are...
. Microcystin is a liver toxin produced by blue-green algae and contains a cyclic heptapeptide structure that that interacts with three distinct regions of the surface of the catalytic subunit of PP1. The structure of MCLR does not change when compexed with PP1, but the catalytic subunit of PP1 does in order to avoid steric effectsof Tyr 276 of PP1 and Mdha side chain of MCLR.
Biological Function
PP1 plays a crucial role in the regulation of blood-glucose levels in the liver and glycogen metabolism. PP1 is important to the reciprocal regulation of glycogen metabolism by ensuring the opposite regulation of glycogen breakdown and glycogen synthesis.Phosphorylase a serves a glucose sensor in liver cells. When glucose levels are low, phosphorylase a in its active R state has PP1 bound tightly. This binding to phosphorylase a prevents any phosphatase activity of PP1 and maintains the active phosphorylated configuration. Therefore, there phosphorylase a will accelerate glycogen breakdown until adequate levels of glucose are achieved. When glucose concentrations get too high, phosphorylase a is converted to its inactive, T state. By shifting phosphorylase a to its T state, PP1 dissociates from the complex. This dissociation activates glycogen synthase and converts phosphorylase a to phosphorylase b. It should be noted that phosphorylase b does not bind PP1 allowing PP1 to remain activated.
When the muscles of the body signal for the need for glycogen degradation and increased glucose concentration, PP1 will be regulated accordingly. Protein kinase A can reduce the activity of PP1. The glycogen binding region, GM becomes phosporylated which causes its dissociation from the catalytic PP1 unit. This separation of the catalytic PP1 unit, glycogen, and other substrates causes a significant decrease in dephosphorylation. Also, when other substrates become phosphorylated by protein kinase A, they can bind to the catalytic subunit of PP1 and directly inhibit it. In the end, phophorylase is kept its active form and glycogen synthase in its inactive form.
Disease Relevance
In Alzheimer’s, hyperphosphorylation of the microtubuleMicrotubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
-associated protein inhibits the assembly of microtubules in neurons. Researchers at the New York State Institute for Basic Research in Developmental Disabilities showed that there is significantly lower type 1 phosphatase activity in both gray and white matters in Alzheimer disease brains. This suggests that phosphatases play a key role in the onset of Alzheimer's.
Regulation of HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
-1 transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
by Protein Phosphatase 1 (PP1). It has been recognized that protein phosphatase-1 (PP1) serves as an important regulator of HIV-1 transcription. Researchers at Howard University showed that Tat
Tat
Tat or TAT may refer to:in ethnology:* Tats, an Iranian ethnic group from the Caucasus* Tat language , their language* Juhuri language, the Jewish Tat language* Tati language , a group of northwestern Iranian dialects...
protein targets PP1 to the nucleus and the consequent interact is important for HIV-1 transcription.
Additional Information
- catalytic subunit: PPP1CAPPP1CASerine/threonine-protein phosphatase PP1-alpha catalytic subunit is an enzyme that in humans is encoded by the PPP1CA gene.-Interactions:...
, PPP1CBPPP1CBSerine/threonine-protein phosphatase PP1-beta catalytic subunit is an enzyme that in humans is encoded by the PPP1CB gene.-Interactions:PPP1CB has been shown to interact with PPP1R15A, Nucleolin, SMARCB1 and PPP1R9B.-Further reading:...
, PPP1CCPPP1CCSerine/threonine-protein phosphatase PP1-gamma catalytic subunit is an enzyme that in humans is encoded by the PPP1CC gene.-Interactions:PPP1CC has been shown to interact with PPP1R15A, SMARCB1, TLX1 and PPP1R9B.-Further reading:... - regulatory (inhibitor) subunit 1: PPP1R1A, PPP1R1BPPP1R1BProtein phosphatase 1 regulatory subunit 1B , also known as dopamine- and cAMP-regulated neuronal phosphoprotein , is a protein that in humans is encoded by the PPP1R1B gene.- Function :...
, PPP1R1C - regulatory (inhibitor) subunit 2: PPP1R2PPP1R2Protein phosphatase inhibitor 2 is an enzyme that in humans is encoded by the PPP1R2 gene.-Interactions:PPP1R2 has been shown to interact with LMTK2 and PPP1R9B.-Further reading:...
- regulatory (inhibitor) subunit 3: PPP1R3APPP1R3AProtein phosphatase 1 regulatory subunit 3A is an enzyme that in humans is encoded by the PPP1R3A gene.-Further reading:...
, PPP1R3B, PPP1R3CPPP1R3CProtein phosphatase 1 regulatory subunit 3C also known as PTG is an enzyme that in humans is encoded by the PPP1R3C gene.- Function :...
, PPP1R3D, PPP1R3E, PPP1R3F, PPP1R3G - regulatory (inhibitor) subunit 7: PPP1R7PPP1R7Protein phosphatase 1 regulatory subunit 7 is an enzyme that in humans is encoded by the PPP1R7 gene.-Further reading:...
- regulatory (inhibitor) subunit 8: PPP1R8PPP1R8Nuclear inhibitor of protein phosphatase 1 is an enzyme that in humans is encoded by the PPP1R8 gene.-Interactions:PPP1R8 has been shown to interact with PPP1CA, Histone deacetylase 2, SF3B1 and EED.-Further reading:...
- regulatory (inhibitor) subunit 9: PPP1R9APPP1R9ANeurabin-1 is a protein that in humans is encoded by the PPP1R9A gene.-Further reading:...
, PPP1R9BPPP1R9BNeurabin-2 is a protein that in humans is encoded by the PPP1R9B gene.-Interactions:PPP1R9B has been shown to interact with PPP1CB, PPP1CA, Dopamine receptor D2, P16, PPP1CC, T-cell lymphoma invasion and metastasis-inducing protein 1 and PPP1R2.... - regulatory (inhibitor) subunit 10: PPP1R10PPP1R10Serine/threonine-protein phosphatase 1 regulatory subunit 10 is an enzyme that in humans is encoded by the PPP1R10 gene.-Further reading:...
- regulatory (inhibitor) subunit 11: PPP1R11PPP1R11Protein phosphatase 1 regulatory subunit 11 is an enzyme that in humans is encoded by the PPP1R11 gene.-Further reading:...
- regulatory (inhibitor) subunit 12: PPP1R12APPP1R12AProtein phosphatase 1 regulatory subunit 12A is an enzyme that in humans is encoded by the PPP1R12A gene.-Interactions:PPP1R12A has been shown to interact with Interleukin 16.-External links:* Info with links in the...
, PPP1R12BPPP1R12BProtein phosphatase 1 regulatory subunit 12B is an enzyme that in humans is encoded by the PPP1R12B gene.-Interactions:PPP1R12B has been shown to interact with Interleukin 16.-Further reading:...
, PPP1R12C - regulatory (inhibitor) subunit 13: PPP1R13BPPP1R13BApoptosis-stimulating of p53 protein 1 is a protein that in humans is encoded by the PPP1R13B gene.-Further reading:...
- regulatory (inhibitor) subunit 14: PPP1R14APPP1R14AProtein phosphatase 1 regulatory subunit 14A also known as CPI-17 is a protein that in humans is encoded by the PPP1R14A gene.- Function :...
, PPP1R14BPPP1R14BProtein phosphatase 1 regulatory subunit 14B is an enzyme that in humans is encoded by the PPP1R14B gene.-Further reading:...
, PPP1R14CPPP1R14CProtein phosphatase 1 regulatory subunit 14C is an enzyme that in humans is encoded by the PPP1R14C gene.-Further reading:...
, PPP1R14D - regulatory (inhibitor) subunit 15: PPP1R15APPP1R15AProtein phosphatase 1 regulatory subunit 15A is an enzyme that in humans is encoded by the PPP1R15A gene.-Interactions:PPP1R15A has been shown to interact with PPP1CB, PPP1CA, PPP1CC, SMARCB1, LYN, TSN, BAG1 and MLL.-Further reading:...
, PPP1R15B - regulatory (inhibitor) subunit 16: PPP1R16A, PPP1R16B