Details for: PPP1R3A

Gene ID: 5506

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: PPP1R3A

Ensembl ID: ENSG00000154415

Description: protein phosphatase 1 regulatory subunit 3A

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • fast muscle cell CL0000190
    CSI 3.33
    rCSI 13.02%
    PRS 95.76
  • muscle cell CL0000187
    CSI 2.5
    rCSI 5.14%
    PRS 98.62
  • cardiac muscle cell CL0000746
    CSI 2.17
    rCSI 3.11%
    PRS 97.66
  • regular atrial cardiac myocyte CL0002129
    CSI 1.69
    rCSI 5.43%
    PRS 98.32
  • regular ventricular cardiac myocyte CL0002131
    CSI 0.98
    rCSI 6.11%
    PRS 97.87

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [PPP1R3A](/details-gene/5506), or Protein Phosphatase 1 Regulatory Subunit 3A, encodes a key regulatory protein that targets protein phosphatase-1 (PP1) to glycogen particles. This function is central to the control of glycogen metabolism. Its expression is highly specific and abundant in muscle tissues, including skeletal and cardiac muscle, underscoring its critical role in energy storage and utilization in these high-demand cell types. Clinically, genetic variants in [PPP1R3A](/details-gene/5506) have been associated with insulin resistance and type 2 diabetes ([OMIM: 600917](https://omim.org/entry/600917)), highlighting its importance in systemic glucose homeostasis ([Link](https://doi.org/10.2337/diabetes.47.9.1519); [Link](https://doi.org/10.1093/hmg/4.8.1313)). ## Cellular Roles and Expression Landscape **Overall**, the expression profile of [PPP1R3A](/details-gene/5506) demonstrates a highly specialized role in muscle physiology. The gene shows its highest significance in [fast muscle cell](/details-cell/CL0000190)s (CSI: 3.33) and more general [muscle cell](/details-cell/CL0000187) populations (CSI: 2.50), identifying it as a defining marker for skeletal muscle. Furthermore, its significant expression in various cardiac cell types, including [cardiac muscle cell](/details-cell/CL0000746) (CSI: 2.17), [regular atrial cardiac myocyte](/details-cell/CL0002129) (CSI: 1.69), and [regular ventricular cardiac myocyte](/details-cell/CL0002131) (CSI: 0.98), indicates a conserved and crucial function in managing glycogen stores for cardiac contractility and function. The collective data suggest that [PPP1R3A](/details-gene/5506) is a workhorse gene essential for the metabolic integrity of both skeletal and cardiac muscle tissues. ## Pathways and Molecular Function The function of [PPP1R3A](/details-gene/5506) is tightly linked to the regulation of energy storage. According to Gene Ontology annotations, it is a key participant in the **glycogen metabolic process** ([GO:0005977](https://www.ebi.ac.uk/QuickGO/term/GO:0005977)) and, more specifically, the **regulation of glycogen biosynthetic process** ([GO:0005979](https://www.ebi.ac.uk/QuickGO/term/GO:0005979)). Its molecular mechanism involves dual binding capabilities. It physically interacts with glycogen through its **glycogen binding** domain ([GO:2001069](https://www.ebi.ac.uk/QuickGO/term/GO:2001069)) and simultaneously recruits its catalytic partner via **protein phosphatase 1 binding** ([GO:0008157](https://www.ebi.ac.uk/QuickGO/term/GO:0008157)). This forms a **protein phosphatase type 1 complex** ([GO:0000164](https://www.ebi.ac.uk/QuickGO/term/GO:0000164)), often localized to cellular membranes ([GO:0016020](https://www.ebi.ac.uk/QuickGO/term/GO:0016020)) where glycogen metabolism is regulated. By tethering PP1 to glycogen, [PPP1R3A](/details-gene/5506) facilitates the dephosphorylation and activation of glycogen synthase, thereby promoting glycogen synthesis. This function is consistent with its high expression in [muscle cell](/details-cell/CL0000187)s, which are primary sites for glycogen storage. ## Research Directions The established link between [PPP1R3A](/details-gene/5506) variants and metabolic disease provides a strong foundation for further investigation into its precise role in both physiology and pathology. **Testable Hypotheses:** 1. Specific polymorphisms in [PPP1R3A](/details-gene/5506), such as the widespread variant at codon 905, functionally impair its ability to form a stable complex with PP1 in [muscle cell](/details-cell/CL0000187)s. This impairment leads to reduced glycogen synthase activity and contributes directly to the cellular phenotype of insulin resistance, as previously suggested ([Link](https://doi.org/10.1093/hmg/4.8.1313)). 2. Given its high expression in [cardiac muscle cell](/details-cell/CL0000746)s, loss-of-function variants in [PPP1R3A](/details-gene/5506) may predispose individuals to glycogen storage-related cardiomyopathies or exacerbate cardiac dysfunction under conditions of metabolic stress, such as ischemia, by limiting the heart's ability to mobilize glycogen stores efficiently. **Key Experimental Approach:** To test hypothesis 1, one could use CRISPR-Cas9 to engineer the codon 905 variant into a human myoblast cell line. Following differentiation into mature myotubes, a series of functional assays would be performed. Co-immunoprecipitation experiments could directly assess whether the variant reduces the binding affinity between [PPP1R3A](/details-gene/5506) and PP1. Subsequently, enzymatic assays measuring glycogen synthase activity and quantification of cellular glycogen content under basal and insulin-stimulated conditions would determine the functional consequence of this altered interaction on glycogen metabolism. **Therapeutic Potential:** As loss-of-function in [PPP1R3A](/details-gene/5506) is associated with insulin resistance, a therapeutic strategy would likely focus on **activation or functional restoration**. Its high tissue specificity to muscle is advantageous, potentially minimizing off-target effects. The development of small-molecule chaperones or activators designed to stabilize the PPP1R3A-PP1 complex or enhance its catalytic efficiency could represent a novel therapeutic avenue. Such a compound could potentially improve insulin sensitivity and glucose uptake specifically in muscle tissue, offering a targeted approach for treating type 2 diabetes.

Genular Protein ID: 1335706204

Symbol: PPR3A_HUMAN

Name: Protein phosphatase 1 regulatory subunit 3A

UniProtKB Accession Codes:

Q16821 A0AVQ2 A4D0T6 O43476 Q75LN8 Q7KYM8 Q86UI6

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CAZy 1 CCDS 1 CDD 1 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DisProt 1 EMBL 10 Ensembl 2 ExpressionAtlas 1 GO 6 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PIR 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 RefSeq 1 SIGNOR 1 SMR 1 STRING 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 9726244

Title: A common variant in PPP1R3 associated with insulin resistance and type 2 diabetes.

PubMed ID: 9726244

DOI: 10.2337/diabetes.47.9.1519

PubMed ID: 12853948

Title: The DNA sequence of human chromosome 7.

PubMed ID: 12853948

DOI: 10.1038/nature01782

PubMed ID: 12690205

Title: Human chromosome 7: DNA sequence and biology.

PubMed ID: 12690205

DOI: 10.1126/science.1083423

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 7926294

Title: Sequence of the human glycogen-associated regulatory subunit of type I protein phosphatase and analysis of its coding region and mRNA level in muscle from patients with non-insulin-dependent diabetes.

PubMed ID: 7926294

DOI: 10.2337/diabetes.43.10.1234

PubMed ID: 7581368

Title: A widespread amino acid polymorphism at codon 905 of the glycogen-associated regulatory subunit of protein phosphatase-1 is associated with insulin resistance and hypersecretion of insulin.

PubMed ID: 7581368

DOI: 10.1093/hmg/4.8.1313

PubMed ID: 16959974

Title: The consensus coding sequences of human breast and colorectal cancers.

PubMed ID: 16959974

DOI: 10.1126/science.1133427

Sequence Information:

  • Length: 1122
  • Mass: 125767
  • Checksum: FACB2CEA7C00E75B
  • Sequence:
    • MEPSEVPSQI SKDNFLEVPN LSDSLCEDEE VTFQPGFSPQ PSRRGSDSSE DIYLDTPSSG 
TRRVSFADSF GFNLVSVKEF DCWELPSAST TFDLGTDIFH TEEYVLAPLF DLPSSKEDLM 
QQLQIQKAIL ESTESLLGST SIKGIIRVLN VSFEKLVYVR MSLDDWQTHY DILAEYVPNS 
CDGETDQFSF KIVLVPPYQK DGSKVEFCIR YETSVGTFWS NNNGTNYTFI CQKKEQEPEP 
VKPWKEVPNR QIKGCLKVKS SKEESSVTSE ENNFENPKNT DTYIPTIICS HEDKEDLEAS 
NRNVKDVNRE HDEHNEKELE LMINQHLIRT RSTASRDERN TFSTDPVNFP NKAEGLEKKQ 
IHGEICTDLF QRSLSPSSSA ESSVKGDFYC NEKYSSGDDC THQPSEETTS NMGEIKPSLG 
DTSSDELVQL HTGSKEVLDD NANPAHGNGT VQIPCPSSDQ LMAGNLNKKH EGGAKNIEVK 
DLGCLRRDFH SDTSACLKES TEEGSSKEDY YGNGKDDEEQ RIYLGVNEKQ RKNFQTILHD 
QERKMGNPKI SVAGIGASNR DLATLLSEHT AIPTRAITAD VSHSPRTNLS WEEAVLTPEH 
HHLTSEGSAL GGITGQVCSS RTGNVLRNDY LFQVEEKSGG INSEDQDNSP QHKQSWNVLE 
SQGKSRENKT NITEHIKGQT DCEDVWGKRD NTRSLKATTE ELFTCQETVC CELSSLADHG 
ITEKAEAGTA YIIKTTSEST PESMSAREKA IIAKLPQETA RSDRPIEVKE TAFDPHEGRN 
DDSHYTLCQR DTVGVIYDND FEKESRLGIC NVRVDEMEKE ETMSMYNPRK THDREKCGTG 
NITSVEESSW VITEYQKATS KLDLQLGMLP TDKTVFSENR DLRQVQELSK KTDSDAIVHS 
AFNSDTNRAP QNSSPFSKHH TEISVSTNEQ AIAVENAVTT MASQPISTKS ENICNSTREI 
QGIEKHPYPE SKPEEVSRSS GIVTSGSRKE RCIGQIFQTE EYSVEKSLGP MILINKPLEN 
MEEARHENEG LVSSGQSLYT SGEKESDSSA STSLPVEESQ AQGNESLFSK YTNSKIPYFL 
LFLIFLITVY HYDLMIGLTF YVLSLSWLSW EEGRQKESVK KK