RGD Reference Report - Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme.

General

Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme.
Authors:	Fedoryshchak, Roman O Přechová, Magdalena Butler, Abbey M Lee, Rebecca O'Reilly, Nicola Flynn, Helen R Snijders, Ambrosius P Eder, Noreen Ultanir, Sila Mouilleron, Stephane Treisman, Richard
Citation:	Fedoryshchak RO, etal., Elife. 2020 Sep 25;9:e61509. doi: 10.7554/eLife.61509.
RGD ID:	405650326
Pubmed:	PMID:32975518 (View Abstract at PubMed)
PMCID:	PMC7599070 (View Article at PubMed Central)
DOI:	DOI:10.7554/eLife.61509 (Journal Full-text)
PPP-family phosphatases such as PP1 have little intrinsic specificity. Cofactors can target PP1 to substrates or subcellular locations, but it remains unclear how they might confer sequence-specificity on PP1. The cytoskeletal regulator Phactr1 is a neuronally enriched PP1 cofactor that is controlled by G-actin. Structural analysis showed that Phactr1 binding remodels PP1's hydrophobic groove, creating a new composite surface adjacent to the catalytic site. Using phosphoproteomics, we identified mouse fibroblast and neuronal Phactr1/PP1 substrates, which include cytoskeletal components and regulators. We determined high-resolution structures of Phactr1/PP1 bound to the dephosphorylated forms of its substrates IRSp53 and spectrin αII. Inversion of the phosphate in these holoenzyme-product complexes supports the proposed PPP-family catalytic mechanism. Substrate sequences C-terminal to the dephosphorylation site make intimate contacts with the composite Phactr1/PP1 surface, which are required for efficient dephosphorylation. Sequence specificity explains why Phactr1/PP1 exhibits orders-of-magnitude enhanced reactivity towards its substrates, compared to apo-PP1 or other PP1 holoenzymes.

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Biological Process

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Phactr1	Rat	regulation of modification of postsynaptic structure	involved_in	IDA		PMID:32975518	SynGO
Phactr1	Rat	regulation of modification of postsynaptic structure	involved_in	IMP		PMID:32975518	SynGO

Cellular Component

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Phactr1	Rat	glutamatergic synapse	is_active_in	IDA		PMID:32975518	SynGO
Phactr1	Rat	glutamatergic synapse	is_active_in	IMP		PMID:32975518	SynGO

Objects Annotated

Genes (Rattus norvegicus)

Phactr1 (phosphatase and actin regulator 1)

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Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme.