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MID1 and MID2 homo- and heterodimerise to tether the rapamycin-sensitive PP2A regulatory subunit, alpha 4, to microtubules: implications for the clinical variability of X-linked Opitz GBBB syndrome and other developmental disorders.

BACKGROUND: Patients with Opitz GBBB syndrome present with a variable array of developmental defects including craniofacial, cardiac, and genital anomalies. Mutations in the X-linked MID1 gene, which encodes a microtubule-binding protein, have been found in approximately 50% of Opitz GBBB syndrome patients consistent with the genetically heterogeneous nature of the disorder. A protein highly related to MID1, called MID2, has also been described that similarly associates with microtubules. RESULTS: To identify protein partners of MID1 and MID2 we undertook two separate yeast two-hybrid screens. Using this system we identified Alpha 4, a regulatory subunit of PP2-type phosphatases and a key component of the rapamycin-sensitive signaling pathway, as a strong interactor of both proteins. Analysis of domain-specific deletions has shown that the B-boxes of both MID1 and MID2 mediate the interaction with Alpha 4, the first demonstration in an RBCC protein of a specific role for the B-box region. In addition, we show that the MID1/2 coiled-coil motifs mediate both homo- and hetero-dimerisation, and that dimerisation is a prerequisite for association of the MID-Alpha 4 complex with microtubules. CONCLUSIONS: Our findings not only implicate Alpha 4 in the pathogenesis of Opitz GBBB syndrome but also support our earlier hypothesis that MID2 is a modifier of the X-linked phenotype. Of further note is the observation that Alpha 4 maps to Xq13 within the region showing linkage to FG (Opitz-Kaveggia) syndrome. Overlap in the clinical features of FG and Opitz GBBB syndromes warrants investigation of Alpha 4 as a candidate for causing FG syndrome.

Pubmed ID: 11806752

Authors

  • Short KM
  • Hopwood B
  • Yi Z
  • Cox TC

Journal

BMC cell biology

Publication Data

September 23, 2002

Associated Grants

None

Mesh Terms

  • Amino Acid Motifs
  • Binding Sites
  • Dimerization
  • Genetic Diseases, X-Linked
  • Humans
  • Ligases
  • Microtubule Proteins
  • Microtubule-Associated Proteins
  • Microtubules
  • Nuclear Proteins
  • Phosphoprotein Phosphatases
  • Phosphorylation
  • Protein Binding
  • Protein Subunits
  • Regulatory Sequences, Nucleic Acid
  • Sequence Deletion
  • Serine
  • Signal Transduction
  • Sirolimus
  • Smith-Lemli-Opitz Syndrome
  • Threonine
  • Transcription Factors
  • Two-Hybrid System Techniques