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PPP1R14B

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Protein Phosphatase 1 Regulatory Inhibitor 14B is a protein encoded by the PPP1R14B gene. The function of the PPP1R14B protein is an inhibitor of PPP1CA. It has over 50-fold higher inhibitory activity when phosphorylated.[1]

Gene

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The PPP1R14B gene's aliases are Phospholipase C-beta-3 Neighboring Gene Protein, PLCB3N, PNG, SOM172, and PHI-1. PPP1R14B is located on the cytogenic band 11q13.1. It's orientation is on the minus strand with FKBP2 and PLCB3 as neighboring genes.[2] It has a total of 4 exons and has a size of 2,463 bases.

Proteins

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Compositional and Charge Distributional Analysis of PPP1R14B[3]

The PPP1R14B protein has a molecular weight (MW) of 15.9 kdal and a pI of 4.75. The N-terminus of the PPP1R14B protein is glycine-rich. There is one domain identified in the PPP1R14B protein and it is the PP1-Inhibitor. There is a negative charge cluster from amino acid 84 to 107 with 0 positive, 13 negative, and 11 neutral amino acids. This negative charge cluster is located near the middle of the PP1-Inhibitor.[4]

Structure

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Chou and Fasman proposed secondary structure of PPP1R14B[5]
 
Phyre2 proposed tertiary structure of PPP1R14B[6] Blue end is N-terminus and red end is C-terminus.

The proposed secondary structure and tertiary structure of PPP1R14B from Chou and Fasman, and Phyre 2 show similar results. The N-terminus of PPP1R14B is proposed to have no secondary or tertiary structure. This correlates with the glycine-rich portion of the N-terminus in PPP1R14B. PPP1R14B has no known transmembrane helices.[7]

Gene Level Regulation

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Promoter

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The promoter for PPP1R14B is called hg 38 promoter.[8] It runs through the PPP1R14B gene and helps to promote neighboring genes as well. The hg 38 promoter is 16,668 base pairs and contains many transcription factor binding sites, DNase clusters, and one CpG island that is associated with the PPP1R14B gene. DNase Clusters 25, 92 and 95 were black, indicating that these regions are highly hypersensitive regions. They all had a cluster score of 1000 and had a genomic size of 350, 550, and 750 respectively. The CpG island was CpG Island 143 with a genomic size of 1569.

Transcription Factor Binding Sites

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Transcription Factor Binding Sites Function
SMARCA 4 Makes a protein called BRG1, which forms several protein groupings called SWI/SNF protein complexes and regulates protein activity by chromatin remodeling.[9]
EGR1 Transcriptional Regulator[10]
FOS Encodes leucine zipper proteins that can form transcription factor complex AP-1 by dimerizing with proteins of the JUN family. Known to regulate cell proliferation, differentiation, and transformation.[11]
TFAP2C AKA Transcription Factor AP-2 Gamma. Encodes a a sequence-specific DNA binding transcription factor involved in activation of several developmental genes. Helps in development of eyes, face, body, wall, limbs and neural tubes.[12]


Expression Pattern

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[13]

The PPP1R14B protein is ubiquitously expressed in most tissues. The image from NCBI shows the expression levels of PPP1R14B in normal tissues.

Protein Level Regulation

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Utilizing the Group Based Prediction system, phosphorylation sites were identified on the PPP1R14B protein sequence.[14] Some sites were experimented and confirmed by the data given by the NCBI page of PPP1R14B protein. These phosphorylation sites can change the conformation of the PPP1R14B protein, as well as help regulate and maintain protein activity and function. The inhibitory activity of the PP1-Inhibitor is increased 50-fold when phosphorylated.

Predicted glycation sites were identified utilizing the NetGlycate program. The positions that were predicted to be glycation sites were positions 114, 140, 146, and 147. All these scores were above the threshold of zero at values of 0.768, 0.717, 0.821, 0.846 respectively. Glycation is a common form of post-translational modification and is required for the function of a mature protein.[15]

Glycosylation sites were predicted on the PPP1R14B sequence. The positions exceeded the 0.5 threshold of the NetOGlyc program. The values were 0.57 for position 22, 0.56 for position 26 and 0.51 for position 108.[16] Glycosylation plays an important role in protein structure, function and stability.[17]

Phosphorylation sites were predicted using the NetPhos server.[18] 7 phosphorylation sites were predicted, some with specific kinases to phosphorylate the specific positions. The threonine on position 6 specified the kinase CKI, the serine at 21 was unspecified, the serine at 32 specified cdk5 and p38MAPK, the threonine at 57 specifies PKC, the serine at 105 specifies CKII, the serine at 142 specifies PKC and cdc2, and the threonine at 143 specifies PKC and p38MAPK.  

The cleavage site between position 36 and 37 was identified on TatP 1.0 server.[19] There is a potential Tat signal, but no Tat motif was found. Cleavage sites can be used to restore natural protein sequences, or inactivate a protein. YinYang sites were identified with the YinOYang 1.2 Server.[20] The YinYang sites identified above can be O-GlcNAcylated and phosphorylated at different times in the cell.  

Homology

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Table of Orthologs
Genus and Species Common Name Taxonomic Group Date of Divergence(MYA) Accession # Sequence Length (AA) Sequence Identity % Sequence Similarity %
Bison bison bison American Bison Mammalia 96 XP_010836393.1 143 69.5 71.4
Gekko japonicus Schlegel's Japanese gecko Reptilia 312 XP_015272304.1 137 77.7 84.5
Xenopus laevis African Clawed Frog Amphibia 351.8 NP_001090486.1 129 67.8 73.8
Danio rerio Zebrafish Actinopterygii 435 NP_001002692.1 128 65.3 74.1
Drosophila melanogaster Common Fruit Fly Insecta 797 NP_001285813.1 124 25 39.4
Hydra vulgaris fresh-water polyp Hydrozoa 824 XP_002159470.1 122 27.3 39.4
 
Rate of evolution compared to fibrinogen alpha chain and cytochrome c

The closest ortholog to the PPP1R14B in humans are Mammalia. The most distant ortholog is the Fresh-water polyp which is a Hydrozoa with a date of divergence of 824 MYA. THe sequence identity is 27.3% and the sequence similarity is 39.4%. From the Date of Divergence vs. Corrected Divergence graph, it can be seen that the evolution of the PPP1R14B gene is relatively slow.

Clinical Significance

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PPP1R14B is known to help patients with cardiac dysfunction, mainly due to the domain within PPP1R14B, PP1-Inhibitor.[21]

  1. ^ "PPP1R14B Gene - GeneCards | PP14B Protein | PP14B Antibody". www.genecards.org. Retrieved 2020-05-03.
  2. ^ "PPP1R14B Gene - GeneCards | PP14B Protein | PP14B Antibody". www.genecards.org. Retrieved 2020-05-03.
  3. ^ "SAPS Results". www.ebi.ac.uk. Retrieved 2020-05-03.
  4. ^ "SAPS Results". www.ebi.ac.uk. Retrieved 2020-05-03.
  5. ^ "PPP1R14B Gene - GeneCards | PP14B Protein | PP14B Antibody". www.genecards.org. Retrieved 2020-05-03.
  6. ^ "PPP1R14B Gene - GeneCards | PP14B Protein | PP14B Antibody". www.genecards.org. Retrieved 2020-05-03.
  7. ^ "5E9E1CCA000027D9C1196F01 expired". www.cbs.dtu.dk. Retrieved 2020-05-03.
  8. ^ "Human hg38 chr11:64,243,717-64,249,966 UCSC Genome Browser v397". genome.ucsc.edu. Retrieved 2020-05-04.
  9. ^ Reference, Genetics Home. "SMARCA4 gene". Genetics Home Reference. Retrieved 2020-05-04.
  10. ^ "EGR1 Gene - GeneCards | EGR1 Protein | EGR1 Antibody". www.genecards.org. Retrieved 2020-05-04.
  11. ^ "FOS Gene - GeneCards | FOS Protein | FOS Antibody". www.genecards.org. Retrieved 2020-05-04.
  12. ^ "TFAP2C Gene - GeneCards | AP2C Protein | AP2C Antibody". www.genecards.org. Retrieved 2020-05-04.
  13. ^ "PPP1R14B protein phosphatase 1 regulatory inhibitor subunit 14B [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-05-04.
  14. ^ "GPS 5.0 - Kinase-specific Phosphorylation Site Prediction". gps.biocuckoo.cn. Retrieved 2020-05-04.
  15. ^ "NetGlycate 1.0 Server - prediction results". www.cbs.dtu.dk. Retrieved 2020-05-04.
  16. ^ "NetOGlyc 4.0 Output format". www.cbs.dtu.dk. Retrieved 2020-05-04.
  17. ^ Arey, Brian J. (2012-09-26). "The Role of Glycosylation in Receptor Signaling". Glycosylation. doi:10.5772/50262.
  18. ^ "NetPhos 3.1 Server - prediction results". www.cbs.dtu.dk. Retrieved 2020-05-04.
  19. ^ "TatP 1.0 Server - prediction results". www.cbs.dtu.dk. Retrieved 2020-05-04.
  20. ^ "YinOYang 1.2 Server - prediction results". www.cbs.dtu.dk. Retrieved 2020-05-04.
  21. ^ Nicolaou, Persoulla; Hajjar, Roger J.; Kranias, Evangelia G. (2009-9). "Role of protein phosphatase-1 inhibitor-1 in cardiac physiology and pathophysiology". Journal of molecular and cellular cardiology. 47 (3): 365–371. doi:10.1016/j.yjmcc.2009.05.010. ISSN 0022-2828. PMC 2716438. PMID 19481088. {{cite journal}}: Check date values in: |date= (help)
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