Last update 01 Nov 2024

PPP1R15B

Last update 01 Nov 2024

Basic Info

Synonyms

FLJ14744, PPP1R15B, protein phosphatase 1 regulatory subunit 15B

Introduction

Maintains low levels of EIF2S1 phosphorylation in unstressed cells by promoting its dephosphorylation by PP1.

Drugs associated with PPP1R15B

Raphin1

Target

PPP1R15B

Mechanism

PPP1R15B inhibitors

Active Org.

MRC Laboratory of Molecular Biology

Originator Org.

MRC Laboratory of Molecular Biology

Active Indication

Huntington Disease

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with PPP1R15B

100 Translational Medicine associated with PPP1R15B

0 Patents (Medical) associated with PPP1R15B

Literatures (Medical) associated with PPP1R15B

02 Apr 2024·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

Substrate recruitment via eIF2γ enhances catalytic efficiency of a holophosphatase that terminates the integrated stress response

Q1 · CROSS-FIELD

Article

Author: Labbé, Katherine ; Harding, Heather P ; Zyryanova, Alisa ; George, Ginto ; Ron, David ; Sidrauski, Carmela ; Hao, Qi ; Shetty, Maithili ; Mafi, Amirhossein ; Yan, Yahui

Dephosphorylation of pSer51 of the α subunit of translation initiation factor 2 (eIF2α P ) terminates signaling in the integrated stress response (ISR). A trimeric mammalian holophosphatase comprised of a protein phosphatase 1 (PP1) catalytic subunit, the conserved C-terminally located ~70 amino acid core of a substrate-specific regulatory subunit (PPP1R15A/GADD34 or PPP1R15B/CReP) and G-actin (an essential cofactor) efficiently dephosphorylate eIF2α P in vitro. Unlike their viral or invertebrate counterparts, with whom they share the conserved 70 residue core, the mammalian PPP1R15s are large proteins of more than 600 residues. Genetic and cellular observations point to a functional role for regions outside the conserved core of mammalian PPP1R15A in dephosphorylating its natural substrate, the eIF2 trimer. We have combined deep learning technology, all-atom molecular dynamics simulations, X-ray crystallography, and biochemistry to uncover binding of the γ subunit of eIF2 to a short helical peptide repeated four times in the functionally important N terminus of human PPP1R15A that extends past its conserved core. Binding entails insertion of Phe and Trp residues that project from one face of an α-helix formed by the conserved repeats of PPP1R15A into a hydrophobic groove exposed on the surface of eIF2γ in the eIF2 trimer. Replacing these conserved Phe and Trp residues with Ala compromises PPP1R15A function in cells and in vitro. These findings suggest mechanisms by which contacts between a distant subunit of eIF2 and elements of PPP1R15A distant to the holophosphatase active site contribute to dephosphorylation of eIF2α P by the core PPP1R15 holophosphatase and to efficient termination of the ISR in mammals.

01 Feb 2024·Molecular Cell

Recruitment of trimeric eIF2 by phosphatase non-catalytic subunit PPP1R15B

Article

Author: Lorenz, Sonja ; Bertolotti, Anne ; Andreeva, Antonina ; van Slegtenhorst, Marjon ; Hodgson, George ; Fatalska, Agnieszka ; Freund, Stefan M V ; Morgan, Tomos ; Thorkelsson, Sigurdur R ; Kaat, Laura Donker ; Maslen, Sarah L

Regulated protein phosphorylation controls most cellular processes. The protein phosphatase PP1 is the catalytic subunit of many holoenzymes that dephosphorylate serine/threonine residues. How these enzymes recruit their substrates is largely unknown. Here, we integrated diverse approaches to elucidate how the PP1 non-catalytic subunit PPP1R15B (R15B) captures its full trimeric eIF2 substrate. We found that the substrate-recruitment module of R15B is largely disordered with three short helical elements, H1, H2, and H3. H1 and H2 form a clamp that grasps the substrate in a region remote from the phosphorylated residue. A homozygous N423D variant, adjacent to H1, reducing substrate binding and dephosphorylation was discovered in a rare syndrome with microcephaly, developmental delay, and intellectual disability. These findings explain how R15B captures its 125 kDa substrate by binding the far end of the complex relative to the phosphosite to present it for dephosphorylation by PP1, a paradigm of broad relevance.

01 Sep 2023·Journal of Cell Communication and Signaling

mir-98-5p regulates gluconeogenesis and lipogenesis by targeting PPP1R15B in hepatocytes

Article

Author: Datta, Malabika ; Khan, Rukshar ; Verma, Amit Kumar

AbstractSeveral reports suggest that circulatory miRNAs are deregulated in diverse diseases and used as markers for disease diagnosis and prognosis. Here we show that miR-98-5p, that is down-regulated in the circulation during diabetes, regulates hepatic gluconeogenesis and lipogenesis by targeting PPP1R15B. miR-98-5p overexpression significantly decreased the transcript and protein levels of PPP1R15B in hepatic HepG2 cells and increased p-eIF2α expression and these were prevented in the presence of its inhibitor. Two major hepatic hallmarks during diabetes i.e. hepatic lipid accumulation and glucose output were explored towards physiological relevance. As compared to scramble, overexpression of miR-98-5p decreased the transcript levels of both gluconeogenic and lipogenic genes together with a significant reduction in hepatic glucose production and fat accumulation in HepG2 cells. Using PASTAA to detect common transcription factors regulating these altered genes, CREB emerged as the most significantly enriched transcription factor. While miR-98-5p overexpression did not change the transcript levels of CREB, there was a significant change in its protein levels. While similar effects on gluconeogenic and lipogenic gene expression were detected using the PPP1R15B siRNA, the opposite was observed in the presence of miR-98-5p inhibitor alone. All these suggest that by targeting PPP1R15B, miR-98-5p regulates hepatic steatosis and glucose output; deregulation of which are characteristic hepatic features during diabetes. Therapeutic intervention of the miR-98/PPP1R15B axis might offer a potential strategy to target aberrant hepatic metabolism during diabetes.Graphical Abstract

Analysis

Perform a panoramic analysis of this field.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

PPP1R15B

Basic Info

Related

Analysis