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

Short, Kieran M; Hopwood, Blair; Yi, Zou; Cox, Timothy C

doi:10.1186/1471-2121-3-1

Cited by 137Genetics and Neurodevelopmental DisordersGenomics and Rare DiseasesMicrotubule and mitosis dynamics

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

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Short, Kieran M, Hopwood, Blair, Yi, Zou, Cox, Timothy C·2002·BMC Cell Biology

DOI 10.1186/1471-2121-3-1PMC PMC64779

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Abstract

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.

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α4 binds partially folded PP2A/C, stabilizing it in a latent state and preventing its ubiquitination and degradation by MID1.
“It has been shown that partially folded PP2A/C is stabilized for latency by the binding of α4, which in part prevents its ubiquitination and subsequent degradation by Midline 1 (MID1) (Jiang et al., 2013; Liu et al., 2001; Short et al., 2002).”
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Authors: Short, K. M., Hopwood, B., Yi, Z., & Cox, T. C.
Affiliations: The University of Adelaide (AU)
Women's and Children's Hospital (AU)
Corresponding author: Cox, Timothy C
ORCID: Short, Kieran M
Cox, Timothy C
Venue: BMC Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2002-01-04
Volume: 3
Issue: 1
Pages: 1-1
ISSN: 1471-2121 (ISSN-L)
DOI: 10.1186/1471-2121-3-1
PMC: PMC64779
OpenAlex: W2111051650
Cited by: 137
References: 38
Citations by year: 2026: 4 · 2025: 2 · 2024: 5 · 2023: 6 · 2022: 4 · 2021: 3 · 2020: 5 · 2019: 7 · 2018: 2 · 2017: 8 · 2016: 5 · 2015: 5 · 2014: 5 · 2013: 8 · 2012: 7
FWCI: 5.32
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: BMC Cell Biology (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, other-oa)
PubMed Central (publishedVersion, other-oa)
PubMed (publishedVersion)
Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Medical Research Council
National Health and Medical Research Council (997706, 157958)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
Keywords: MID1, Mid2, FG syndrome, microtubule binding, protein dimerization, B-box, coiled-coil domain, protein-protein interaction, Xq13
MeSH terms: Binding Sites, Humans, Ligases, Microtubule Proteins, Microtubule-Associated Proteins, Microtubules, Nuclear Proteins, Phosphoprotein Phosphatases, Phosphorylation, Protein Binding, Regulatory Sequences, Nucleic Acid, Serine, Threonine, Transcription Factors, Signal Transduction, Sequence Deletion, Smith-Lemli-Opitz Syndrome, Dimerization, Sirolimus, Two-Hybrid System Techniques, Amino Acid Motifs, Protein Subunits, Genetic Diseases, X-Linked, Ubiquitin-Protein Ligases

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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

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