MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation

Nat Genet. 2001 Nov;29(3):287-94. doi: 10.1038/ng762.

Abstract

The gene MID1, the mutation of which causes X-linked Opitz G/BBB syndrome (OS, MIM 300000), encodes a microtubule-associated protein (MAP). We show that mutation of MID1 leads to a marked accumulation of the catalytic subunit of protein phosphatase 2A (PP2Ac), a central cellular regulator. PP2Ac accumulation is caused by an impairment of a newly identified E3 ubiquitin ligase activity of the MID1 protein that normally targets PP2Ac for degradation through binding to its alpha4 regulatory subunit in an embryonic fibroblast line derived from a fetus with OS. Elevated PP2Ac causes hypophosphorylation of MAPs, a pathological mechanism that is consistent with the OS phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Antibody Complex
  • Binding Sites
  • Blotting, Western
  • COS Cells
  • Fibroblasts
  • Fluorescent Antibody Technique
  • Humans
  • Ligases / genetics*
  • Ligases / immunology
  • Ligases / metabolism*
  • Microtubule Proteins*
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Microtubules / chemistry
  • Microtubules / metabolism
  • Models, Biological
  • Mutation*
  • Nuclear Proteins*
  • Phosphoprotein Phosphatases / chemistry
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • Polyubiquitin / metabolism
  • Precipitin Tests
  • Protein Binding
  • Protein Phosphatase 2
  • Protein Subunits
  • Substrate Specificity
  • Syndrome
  • Transcription Factors / genetics*
  • Transcription Factors / immunology
  • Transcription Factors / metabolism*
  • Two-Hybrid System Techniques
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases
  • Up-Regulation

Substances

  • Antigen-Antibody Complex
  • Microtubule Proteins
  • Microtubule-Associated Proteins
  • Nuclear Proteins
  • Protein Subunits
  • Transcription Factors
  • Ubiquitin
  • Polyubiquitin
  • Mid1 protein, human
  • Ubiquitin-Protein Ligases
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2
  • Ligases

Associated data

  • OMIM/145410
  • OMIM/300000