Proteomics

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Recruitment of trimeric eIF2 by phosphatase non-catalytic subunit PPP1R15B

ABSTRACT: HDX-MS of R15B and it's interactions with trimeric eIF2 substrate. Here we integrated diverse approaches to elucidate how the PP1 non-catalytic subu-nit 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 re-gion remote from the phosphorylated residue. A homozygous N423D variant, adja-cent to H1, reducing substrate binding and dephosphorylation was discovered in a ra-re syndrome with microcephaly, development 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 phospho-site to present it for dephosphorylation by PP1, a paradigm of broad relevance.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture

SUBMITTER: Tomos Morgan  

LAB HEAD: Anne Bertolotti

PROVIDER: PXD047538 | Pride | 2024-05-22

REPOSITORIES: Pride

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Dataset's files

Source:
Action DRS
R15B.csv Csv
R15B_1min_1.zip Other
R15B_1min_2.zip Other
R15B_1min_3.zip Other
R15B_30sec_1.zip Other
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Publications

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 e  ...[more]

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