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

Trockenbacher, Alexander; Suckow, Vanessa; Foerster, John; Winter, Jennifer; Krauß, Sybille; Ropers, Hans‐Hilger; Schneider, Rainer; Schweiger, Susann

doi:10.1038/ng762

Cited by 267 publications

(363 citation statements)

References 47 publications

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“…Through this interaction MID1 ubiquitinates PP2Ac and targets it towards ubiquitin-specific degradation by the proteasome. Therefore, MID1 is a negative regulator of PP2Ac 18 . Through this negative regulatory influence on PP2A activity, MID1 also controls the activity of the mTOR kinase.…”

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confidence: 99%

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

et al. 2013

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Expansion of CAG repeats is a common feature of various neurodegenerative disorders, including Huntington's disease. Here we show that expanded CAG repeats bind to a translation regulatory protein complex containing MID1, protein phosphatase 2A and 40S ribosomal S6 kinase. Binding of the MID1-protein phosphatase 2A protein complex increases with CAG repeat size and stimulates translation of the CAG repeat expansion containing messenger RNA in a MID1-, protein phosphatase 2A-and mammalian target of rapamycindependent manner. Our data indicate that pathological CAG repeat expansions upregulate protein translation leading to an overproduction of aberrant protein and suggest that the MID1-complex may serve as a therapeutic target for the treatment of CAG repeat expansion disorders.

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Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

et al. 2013

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“…MID1 mutant forms reproducing C-terminal mutations found in OS patients show a reduced affinity for the microtubules and are often found in cytoplasmic bodies [Cainarca et al, 1999;Schweiger et al, 1999]. Along the microtubules, MID1 exerts the role of RING finger E3 ubiquitin ligase that regulates phosphatase 2A (PP2A) catalytic subunit degradation [Trockenbacher et al, 2001]. The regulation of PP2A, as well as MID1 phosphorylation status, is mediated by direct interaction between MID1 and a noncatalytic phosphatase subunit, alpha4 [Liu et al, 2001;Short et al, 2002;Trockenbacher et al, 2001].…”

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confidence: 99%

MID1 mutations in patients with X-linked Opitz G/BBB syndrome

2008

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Communicated by Arnold MunnichMutations in the MID1 gene are responsible for the X-linked form of Opitz G/BBB syndrome (OS), a disorder that affects the development of midline structures. OS is characterized by hypertelorism, hypospadias, laryngotracheo-esophageal (LTE) abnormalities, and additional midline defects. Cardiac, anal, and neurological defects are also present. The expressivity of OS is highly variable, even within the same family. We reviewed all the MID1 mutations reported so far, in both familial and sporadic cases. The mutations are scattered along the entire length of the gene and consist of missense and nonsense mutations, insertions and deletions, either inframe or causing frameshifts, and deletions of either single exons or the entire MID1 coding region. The variety of described mutations and the lack of a strict genotype-phenotype correlation confirm the previous suggestion of the OS phenotype being caused by a loss-of-function mechanism. However, although a specific mutation cannot entirely account for the observed phenotype, we observed preferential association between some types of mutation and specific clinical manifestations, e.g., brain anatomical defects and truncating mutations. This may suggest that the pathogenetic mechanism underlying the OS phenotype is more complex and may vary among the affected organs. Hum Mutat 29(5), [584][585][586][587][588][589][590][591][592][593][594] 2008.

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“…Interestingly, MID1 was also shown to polyubiquitylate PP2c and thereby to mark it for degradation (Trockenbacher et al . 2001). However, the cleavage of α4 induced by MID1 releases MID1 from the ternary complex, suggesting that other E3 ligases are responsible for PP2c polyubiquitylation in the absence of associated MID1.…”

Section: Regulation Of Neuronal Proteins By Monoubiquitylationmentioning

confidence: 99%

Protein monoubiquitylation: targets and diverse functions

Nakagawa

Nakayama

2015

Genes to Cells

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Ubiquitin is a 76‐amino acid protein whose conjugation to protein targets is a form of post‐translational modification. Protein ubiquitylation is characterized by the covalent attachment of the COOH‐terminal carboxyl group of ubiquitin to an amino group of the substrate protein. Given that the NH2‐terminal amino group is usually masked, internal lysine residues are most often targeted for ubiquitylation. Polyubiquitylation refers to the formation of a polyubiquitin chain on the substrate as a result of the ubiquitylation of conjugated ubiquitin. The structures of such polyubiquitin chains depend on the specific lysine residues of ubiquitin targeted for ubiquitylation. Most of the polyubiquitin chains other than those linked via lysine‐63 and methionine‐1 of ubiquitin are recognized by the proteasome and serve as a trigger for substrate degradation. In contrast, polyubiquitin chains linked via lysine‐63 and methionine‐1 serve as a binding platform for proteins that function in immune signal transduction or DNA repair. With the exception of a few targets such as histones, the functions of protein monoubiquitylation have remained less clear. However, recent proteomics analysis has shown that monoubiquitylation occurs more frequently than polyubiquitylation, and studies are beginning to provide insight into its biologically important functions. Here, we summarize recent findings on protein monoubiquitylation to provide an overview of the targets and molecular functions of this modification.

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

Cited by 267 publications

References 47 publications

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

MID1 mutations in patients with X-linked Opitz G/BBB syndrome

Protein monoubiquitylation: targets and diverse functions

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