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Mol Cell. 2018 Oct 4;72(1):19-36.e8. doi: 10.1016/j.molcel.2018.08.027. Epub 2018 Sep 20.

Cancer Mutations of the Tumor Suppressor SPOP Disrupt the Formation of Active, Phase-Separated Compartments.

Author information

1
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
2
Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona 08028, Spain.
3
Structural Biology and NMR Laboratory, The Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
4
Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona 08028, Spain; ICREA, Barcelona, Spain.
5
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Molecular Machines and Signaling, Max-Planck Institute of Biochemistry, Martinsried/Munich, Germany; Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
6
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: tanja.mittag@stjude.org.

Abstract

Mutations in the tumor suppressor SPOP (speckle-type POZ protein) cause prostate, breast, and other solid tumors. SPOP is a substrate adaptor of the cullin3-RING ubiquitin ligase and localizes to nuclear speckles. Although cancer-associated mutations in SPOP interfere with substrate recruitment to the ligase, mechanisms underlying assembly of SPOP with its substrates in liquid nuclear bodies and effects of SPOP mutations on assembly are poorly understood. Here, we show that substrates trigger phase separation of SPOP in vitro and co-localization in membraneless organelles in cells. Enzymatic activity correlates with cellular co-localization and in vitro mesoscale assembly formation. Disease-associated SPOP mutations that lead to the accumulation of proto-oncogenic proteins interfere with phase separation and co-localization in membraneless organelles, suggesting that substrate-directed phase separation of this E3 ligase underlies the regulation of ubiquitin-dependent proteostasis.

KEYWORDS:

Cul3; DAXX; NMR; androgen receptor; biomolecular codensates; multivalency; nuclear bodies; polymerization; prostate cancer; ubiquitination

PMID:
30244836
PMCID:
PMC6179159
[Available on 2019-10-04]
DOI:
10.1016/j.molcel.2018.08.027

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