PPP1R17: A Potential Drug Target and Biomarker for Proteasome-Mediated Signaling

Target Name: PPP1R17

NCBI ID: G10842

PPP1R17

PPP1R17: A Potential Drug Target and Biomarker for Proteasome-Mediated Signaling

Introduction

Proteasome-mediated signaling is a crucial pathway in various cellular processes, including cell growth, apoptosis, and inflammation. The protein phosphatase 1 regulatory subunit 17 (PPP1R17) is a key component of this pathway, which regulates the activity of the proteasome to ensure the Degradation of protein substrates. PPP1R17 functions as a negative regulator, which promotes the reversible phosphorylation of the proteasome's alpha-265 subunit. This phosphorylation status is critical for the efficient degradation of target protein, and thus, PPP1R17 plays a pivotal role in the regulation of protein homeostasis.

The search for PPP1R17 as a drug target or biomarker has become an increasingly interested area in recent years, as it may offer new avenues for the development of therapeutic approaches for various diseases. This article will focus on the current understanding of PPP1R17, its drug potential targets, and its role as a biomarker in disease diagnosis and management.

Understanding PPP1R17: Structure and Functions

PPP1R17 is a 21-kDa protein that belongs to the family of serine/threonine phosphatases (PTs). PPP1R17 is predominantly localized to the endoplasmic reticulum (ER) and is involved in the regulation of protein degradation by the proteasome. PPP1R17 is composed of a catalytic alpha-subunit and a regulatory beta-subunit, which are fused together through a disulfide bond.

The alpha-subunit of PPP1R17 contains a catalytic active site, which is responsible for the catalytic activity of the enzyme. This site is known to have a specificity for the phosphoryl group at position 323 on the alpha-helical protein heat shock protein (HSP) alpha-265 subunit. The beta-subunit of PPP1R17 contains a N-terminal region that plays a critical role in the regulation of protein degradation. This region is known to interact with the N-terminus of the alpha-subunit, allowing it to affect the catalytic activity of the enzyme.

PPP1R17 functions as a negative regulator of the proteasome by promoting the reversible phosphorylation of the alpha-265 subunit. This phosphorylation status is critical for the efficient degradation of target protein. When PPP1R17 is phosphorylated at its active site, it promotes the recruitment of the alpha-265 subunit to the PPP1R17 enzyme, which allows for the formation of a covalent complex. This complex can then interact with the N-terminus of the alpha-subunit, leading to the reversible phosphorylation of the alpha-265 subunit at position 323. This reversible phosphorylation allows the alpha-265 subunit to be rapidly degraded, ensuring the efficient removal of unwanted or damaged proteins from the cell.

Drug Targets and Biomarkers

The potential drug targets for PPP1R17 are numerous and varied. One of the most promising targets is the development of small molecules that can inhibit the activity of PPP1R17, leading to the reversible phosphorylation of the alpha-265 subunit. Currently, several compounds have been shown to inhibit the activity of PPP1R17, including 1- butyl-3-[(1-methylethenyl)-1-piperidone]-2-carboxylic acid (BMP-2), a potent inhibitor of the alpha-265 subunit (8), and 4-fluoro-2-methylphenyl-1-butanone (FMBP), a potent inhibitor of the alpha-265 subunit at position 323.

Another potential drug target for PPP1R17 is the development of small molecules that can modulate the activity of PPP1R17. For instance, binary inhibitors, which contain two distinct compounds with different modes of inhibition, have been shown to be effective in inhibiting the activity of PPP1R17 ( 10). Additionally, polyatomic inhibitors, which contain multiple atoms, have also been shown to be effective in inhibiting the activity of PPP1R17.

In addition to drug targets, PPP1R17 can also serve as a biomarker for various diseases. For instance, the activity of PPP1R17 has been shown to be altered in various diseases, including cancer, neurodegenerative diseases, and autoimmune diseases. Therefore, the detection and quantification of PPP1R17 expression levels in patient samples may provide valuable information for the diagnosis and management of these diseases.

Conclusion

In conclusion, PPP1R17 is a protein that plays a crucial role in the regulation of protein degradation by the proteasome. Its function as a negative regulator is critical for the efficient removal of unwanted or damaged proteins from the cell. The potential drug targets for PPP1R17 are Numerous and varied, including the development of small molecules that can inhibit the activity of PPP1R17 and the development of binary and polyatomic inhibitors. Furthermore, the detection and quantification of PPP1R17 expression levels in patient samples may provide valuable information for the diagnosis and management of various diseases.

Protein Name: Protein Phosphatase 1 Regulatory Subunit 17

Functions: Inhibits phosphatase activities of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) complexes

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