MassIVE MSV000088106

Complete Public PXD028612

PP2A/B55a substrate recruitment as defined by the retinoblastoma-related protein p107

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Description

Protein phosphorylation is a reversible post-translation modification essential in cell signaling. This study addresses a long-standing question as to how the most abundant serine/threonine Protein Phosphatase 2 (PP2A) holoenzyme, PP2A/B55a, specifically recognizes substrates and presents them to the enzyme active site. Here, we show how the PP2A regulatory subunit B55a recruits p107, a pRB-related tumor suppressor and B55a substrate. Using molecular and cellular approaches, we identified a conserved region 1 (R1, residues 615-626) encompassing the strongest p107 binding site. This enabled us to identify an "HxRVxxV619-625" short linear motif (SLiM) in p107 as necessary for B55a binding and dephosphorylation of the proximal pSer-615 in vitro and in cells. Numerous B55a/PP2A substrates, including TAU, contain a related SLiM C-terminal from a proximal phosphosite, "p[SSTT]-P--x(4,10)-[RK]-V-x-x-[VII]-R". Mutation of conserved SLiM residues in TAU dramatically inhibits dephosphorylation by PP2A/B55a, validating its generality. A data-guided computational model details the interaction of residues from the conserved p107 SLiM, the B55a groove, and phosphosite presentation. Altogether these data provide key insights into PP2A/B55a mechanisms of substrate recruitment and active site engagement, and also facilitate identification and validation of new substrates, a key step towards understanding PP2A/B55a role in multiple cellular processes. [doi:10.25345/C5426Q] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: phosphorylation ; PP2A ; p107 ; pRB ; TAU ; B55a

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Principal Investigators:
(in alphabetical order) 		Arminja Kettenbach, The Geisel School of Medicine at Dartmouth, United States
Submitting User: madamo
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