Structural basis for the specificity of PPM1H phosphatase for Rab GTPases

Waschbüsch, Dieter; Berndsen, Kerryn; Lis, Pawel; Knebel, Axel; Lam, Yuko PY; Alessi, Dario R.; Khan, Amir R.

doi:10.15252/embr.202152675

Title: Structural basis for the specificity of PPM1H phosphatase for Rab GTPases

Journal Article · Tue Sep 28 00:00:00 EDT 2021 · EMBO Reports

DOI:https://doi.org/10.15252/embr.202152675· OSTI ID:1836772

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^[2]; Knebel, Axel ^[3];

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Trinity College Dublin (Ireland)
University of Dundee (United Kingdom); Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD (United States)
University of Dundee (United Kingdom)
Trinity College Dublin (Ireland); Boston Children's Hospital, MA (United States)

LRRK2 serine/threonine kinase is associated with inherited Parkinson’s disease. LRRK2 phosphorylates a subset of Rab GTPases within their switch 2 motif to control their interactions with effectors. Recent work has shown that the metal-dependent protein phosphatase PPM1H counteracts LRRK2 by dephosphorylating Rabs. PPM1H is highly selective for LRRK2 phosphorylated Rabs, and closely related PPM1J exhibits no activity towards substrates such as Rab8a phosphorylated at Thr72 (pThr72). Here, we have identified the molecular determinant of PPM1H specificity for Rabs. The crystal structure of PPM1H reveals a structurally conserved phosphatase fold that strikingly has evolved a 110-residue flap domain adjacent to the active site. The flap domain distantly resembles tudor domains that interact with histones in the context of epigenetics. Cellular assays, crosslinking and 3-D modelling suggest that the flap domain encodes the docking motif for phosphorylated Rabs. Consistent with this hypothesis, a PPM1J chimaera with the PPM1H flap domain dephosphorylates pThr72 of Rab8a both in vitro and in cellular assays. Therefore, PPM1H has acquired a Rab-specific interaction domain within a conserved phosphatase fold.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); Science Foundation Ireland; Michael J. Fox Foundation for Parkinson’s Research; UK Medical Research Council; National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357; SC0012704; 12/IA/1239; 17298; MC_UU_12016/2; S10OD021527

OSTI ID:: 1836772

Journal Information:: EMBO Reports, Vol. 22, Issue 11; ISSN 1469-221X

Publisher:: European Molecular Biology OrganizationCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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