MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation.
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.
Trockenbacher
A
A
Institute of Biochemistry, Peter-Mayr-Strasse 1a, 6020 Innsbruck, Austria.
Suckow
V
V
Foerster
J
J
Winter
J
J
Krauss
S
S
Ropers
H H
HH
Schneider
R
R
Schweiger
S
S
D000818:Animals; D000936:Antigen-Antibody Complex; D001665:Binding Sites; D015153:Blotting, Western; D019556:COS Cells; D005347:Fibroblasts; D005455:Fluorescent Antibody Technique; D006801:Humans; D008025:Ligases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D008868:Microtubule Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D009687:Nuclear Proteins; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D025821:Polyubiquitin / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D054648:Protein Phosphatase 2; D021122:Protein Subunits; D013379:Substrate Specificity; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation
D000936:Antigen-Antibody Complex; D008868:Microtubule Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D021122:Protein Subunits; D014157:Transcription Factors; D025801:Ubiquitin; D025821:Polyubiquitin; C109052:MID1 protein, human; D044767:Ubiquitin-Protein Ligases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D008025:Ligases