MID1

Last updated
MID1
Protein MID1 PDB 2dq5.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases MID1 , BBBG1, FXY, GBBB1, MIDIN, OGS1, OS, OSX, RNF59, TRIM18, XPRF, ZNFXY, midline 1, GBBB
External IDs OMIM: 300552 MGI: 1100537 HomoloGene: 7837 GeneCards: MID1
Orthologs
SpeciesHumanMouse
Entrez

4281

17318

Ensembl

ENSG00000101871

ENSMUSG00000035299

UniProt

O15344

O70583

RefSeq (mRNA)
RefSeq (protein)

NP_001277433
NP_001277434
NP_001277435
NP_001277441
NP_034927

Location (UCSC) Chr X: 10.45 – 10.83 Mb Chr X: 168.47 – 168.79 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

MID1 is a protein that belongs to the Tripartite motif family (TRIM) and is also known as TRIM18. [5] [6] The MID1 gene is located on the short arm of the X chromosome and loss-of-function mutations in this gene are causative of the X-linked form of a rare developmental disease, Opitz G/BBB Syndrome. [5] [7]

The MID1 gene and its product

The human MID1 gene is located on the short arm of the X chromosome (Xp22.2) and includes 9 coding exons, spanning approximately 400 kb of the genome. [5] [8] Upstream to the first coding exon, the MID1 gene employs alternative 5’ untranslated exons and at least five alternative promoters that drive the transcription of the gene, resulting in several MID1 transcript isoforms. [9] The MID1 gene encodes a 667 amino acid protein that belongs to the TRIM family. MID1 protein consists of a conserved N-terminal tripartite module composed of a RING domain, 2 B-Box domains (B-box 1 and B-box 2) and a coiled-coil region. [5] [6] Within the TRIM family, MID1 belongs to the C-I subgroup characterised by the presence, downstream to the tripartite motif, of a COS domain, a Fibronectin type III (FN3) repeat and a PRY-SPRY domain. [10]

MID1 main cellular functions

MID1 as an E3 ubiquitin ligase

MID1 is a microtubular protein [11] [12] that acts as an ubiquitin E3 ligase in vitro and in cells. Ubiquitination is a type of post-translational modification in which the transfer of one or several ubiquitin peptide molecules to substrates determines their stability and/or activity. [13] The MID1 E3 ubiquitin ligase activity is catalysed by the RING domain, a hallmark of one of the main classes of E3 ubiquitin ligases that, within the ubiquitination cascade, facilitate the transfer of the ubiquitin peptide to specific substrates. [14] [15] [16] Several MID1 E3 ubiquitin ligase targets have been reported: Alpha4 (α4) and its associated phosphatase, PP2A, [14] Fu, [17] Pax6 [18] and BRAF35. [19]

MID1-α4-PP2A complex

Together with α4 and PP2A, MID1 can form a ternary complex in which α4 acts as an adaptor protein. [14] The data so far indicate that MID1 promotes α4 mono-ubiquitination, leading to its calpain-dependent cleavage [20] that in turn causes PP2A catalytic subunit (PP2Ac) polyubiquitination and proteasomal degradation. [14] Since PP2A is involved in many cellular processes, [21] the MID1-α4-PP2A ternary complex may be involved in the regulation of several of them, mainly on microtubules. The complex can modulate mTORC1 signalling; indeed PP2A attenuates mTORC1 activity through dephosphorylation. By lowering PP2Ac levels, MID1 leads to increase mTORC1 signalling. [22] Conversely, the lack or loss-of-function mutations of MID1 lead to increased levels of PP2A and, as a consequence, to a general hypo-phosphorylation of PP2A targets, included mTORC1. The signalling of mTORC1 is implicated in cytoskeletal dynamics, intracellular transport, cell migration, autophagy, protein synthesis, cell metabolism, so it is possible that MID1, by controlling PP2Ac, is ultimately implicated in some of these cellular processes.

MID1 and Sonic Hedgehog

MID1 is also involved is the Sonic Hedgehog (Shh) pathway. [23] MID1 catalyses the ubiquitination and proteasomal-dependent cleavage of Fu, a kinase involved in Hedgehog signalling pathway. [17] The cleavage of the kinase domain of Fu favours the translocation of the transcription factor GLI3A (activator form) in the nucleus. [17] [24] In this way, GLI3A activates the expression of Shh target genes, leading to an increase of Shh signalling. The cross talk between MID1 and the Shh pathway is also supported by experimental evidence in model organisms. [18] [25]

Role and expression during embryonic development

MID1 is nearly ubiquitously expressed in all embryonic tissues, having an important function during development. Several model organisms have been used to study the expression pattern of MID1 transcript at different times of gestation: mouse, [26] [27] chicken, [28] [29] xenopus [18] [30] and also human embryos. [31] At the very early stage of embryonic development, MID1 is expressed in the primitive node where MID1 plays a pivotal role in establishing the molecular asymmetry at the node, which is crucial for the early definition of the laterality as embryonic development progresses. Later in embryogenesis, at the neurulation stage, MID1 transcript is mainly observed in the cranial region of the developing neural folds. Starting from midgestation, the highest levels of MID1 transcript are observed in the proliferating compartments of the central nervous system and in the epithelia of the developing branchial arches, craniofacial processes, optic vesicle, in the heart and in the gastrointestinal and urogenital system.

Clinical significance

The MID1 gene was identified concomitantly with the discovery that it was causatively mutated in patients with a rare genetic disease, the X-linked form of Opitz G/BBB syndrome (XLOS) (OMIM #300000). [5] XLOS is a congenital malformative disorder characterised by defects in the embryonic development of midline structures. XLOS is characterised by high variability of the clinical signs and, being X-linked, males are generally affected. The most frequently observed signs are: dysmorphic features, mainly represented by hypertelorism often associated with cleft lip and palate, frontal bossing, large nasal bridge, and low-set ears. Laryngo-tracheo-esophageal abnormalities are also frequently observed in XLOS patients as well as external genitalia abnormalities that are predominantly represented by various-degree-hypospadias. [32] In addition, XLOS patients can present cardiac abnormalities and anal defects. [32] XLOS also shows a neurological component represented by cerebellar vermis hypoplasia and agenesis or hypoplasia of the corpus callosum accompanied by intellectual disabilities and developmental delays. [32] Since its discovery as the causative gene for XLOS, approximately one hundred different pathogenetic mutations have been described in the MID1 gene. Even though the type and the distribution of mutations suggested a loss-of-function mechanism in the pathogenesis of Opitz syndrome, the aetiology of the disease remains still unclear. Additional clinical conditions are described to be associated with alterations of MID1, given also its implication in a wide variety of cellular mechanisms. In fact, involvement of MID1 in asthma, cancer, and neurodegeneration relevant pathways has been reported.

Notes

Related Research Articles

<span class="mw-page-title-main">Ubiquitin</span> Regulatory protein found in most eukaryotic tissues

Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.

<span class="mw-page-title-main">Ubiquitin ligase</span> Protein

A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.

<span class="mw-page-title-main">UBE3A</span> Protein-coding gene in Homo sapiens

Ubiquitin-protein ligase E3A (UBE3A) also known as E6AP ubiquitin-protein ligase (E6AP) is an enzyme that in humans is encoded by the UBE3A gene. This enzyme is involved in targeting proteins for degradation within cells.

<span class="mw-page-title-main">Von Hippel–Lindau tumor suppressor</span> Mammalian protein found in Homo sapiens

The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that, in humans, is encoded by the VHL gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease, which is characterized by hemangioblastomas of the brain, spinal cord and retina. It is also associated with kidney and pancreatic lesions.

<span class="mw-page-title-main">Ubiquitin-activating enzyme</span> Class of enzymes

Ubiquitin-activating enzymes, also known as E1 enzymes, catalyze the first step in the ubiquitination reaction, which can target a protein for degradation via a proteasome. This covalent bond of ubiquitin or ubiquitin-like proteins to targeted proteins is a major mechanism for regulating protein function in eukaryotic organisms. Many processes such as cell division, immune responses and embryonic development are also regulated by post-translational modification by ubiquitin and ubiquitin-like proteins.

<span class="mw-page-title-main">NEDD4</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase NEDD4, also known as neural precursor cell expressed developmentally down-regulated protein 4 is an enzyme that is, in humans, encoded by the NEDD4 gene.

<span class="mw-page-title-main">NEDD4L</span> Protein-coding gene in the species Homo sapiens

Neural precursor cell expressed developmentally downregulated gene 4-like (NEDD4L) or NEDD4-2 is an enzyme of the NEDD4 family. In human the protein is encoded by the NEDD4L gene. In mouse the protein is commonly known as NEDD4-2 and the gene Nedd4-2.

<span class="mw-page-title-main">BTRC (gene)</span> Protein-coding gene in the species Homo sapiens

F-box/WD repeat-containing protein 1A (FBXW1A) also known as βTrCP1 or Fbxw1 or hsSlimb or pIkappaBalpha-E3 receptor subunit is a protein that in humans is encoded by the BTRC gene.

<span class="mw-page-title-main">CKS1B</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinases regulatory subunit 1 is a protein that in humans is encoded by the CKS1B gene.

<span class="mw-page-title-main">UBE2D1</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 D1 is a protein that in humans is encoded by the UBE2D1 gene.

<span class="mw-page-title-main">UBE2D2</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 D2 is a protein that in humans is encoded by the UBE2D2 gene.

<span class="mw-page-title-main">CUL3</span> Protein-coding gene in humans

Cullin 3 is a protein that in humans is encoded by the CUL3 gene.

<span class="mw-page-title-main">TRIM37</span> Protein-coding gene in the species Homo sapiens

Tripartite motif-containing protein 37 is an E3 ubiquitin ligase in humans that is encoded by the TRIM37 gene.

<span class="mw-page-title-main">UBR1</span> Mammalian protein found in Homo sapiens

The human gene UBR1 encodes the enzyme ubiquitin-protein ligase E3 component n-recognin 1.

<span class="mw-page-title-main">UBE2H</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 H is a protein that in humans is encoded by the UBE2H gene.

<span class="mw-page-title-main">MID2</span> Protein-coding gene in humans

Midline-2 is a protein that in humans is encoded by the MID2 gene.

<span class="mw-page-title-main">TRIM32</span> Protein-coding gene in the species Homo sapiens

Tripartite motif-containing protein 32 is a protein that in humans is encoded by the TRIM32 gene. Since its discovery in 1995, TRIM32 has been shown to be implicated in a number of diverse biological pathways.

<span class="mw-page-title-main">IGBP1</span> Protein-coding gene in the species Homo sapiens

Immunoglobulin-binding protein 1 is a protein that in humans is encoded by the IGBP1 gene.

<span class="mw-page-title-main">Johanson–Blizzard syndrome</span> Medical condition

Johanson–Blizzard syndrome (JBS) is a rare, sometimes fatal autosomal recessive multisystem congenital disorder featuring abnormal development of the pancreas, nose and scalp, with intellectual disability, hearing loss and growth failure. It is sometimes described as a form of ectodermal dysplasia.

Opitz G/BBB syndrome, also known as Opitz syndrome, G syndrome or BBB syndrome, is a rare genetic disorder that will affect physical structures along the midline of the body. The letters G and BBB represent the last names of the families that were first diagnosed with the disorder, while Opitz is the last name of the doctor that first described the signs and symptoms of the disease. There are two different forms of Optiz G/BBB syndrome: x-linked (recessive) syndrome and dominant autosomal syndrome. However, both result in common physical deformities, although their pattern of inheritance may differ. Several other names for the disease(s) are no longer used. These include hypospadias-dysphagia syndrome, Opitz-Frias syndrome, telecanthus with associated abnormalities, and hypertelorism-hypospadias syndrome.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000035299 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 5 Quaderi NA, Schweiger S, Gaudenz K, Franco B, Rugarli EI, Berger W, et al. (November 1997). "Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22". Nature Genetics. 17 (3): 285–91. doi:10.1038/ng1197-285. hdl: 2066/24575 . PMID   9354791. S2CID   5832037.
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  9. ↑ Landry JR, Mager DL (November 2002). "Widely spaced alternative promoters, conserved between human and rodent, control expression of the Opitz syndrome gene MID1". Genomics. 80 (5): 499–508. doi:10.1006/geno.2002.6863. PMID   12408967.
  10. ↑ Short KM, Cox TC (March 2006). "Subclassification of the RBCC/TRIM superfamily reveals a novel motif necessary for microtubule binding". The Journal of Biological Chemistry. 281 (13): 8970–80. doi: 10.1074/jbc.M512755200 . PMID   16434393.
  11. ↑ Schweiger S, Foerster J, Lehmann T, Suckow V, Muller YA, Walter G, et al. (March 1999). "The Opitz syndrome gene product, MID1, associates with microtubules". Proceedings of the National Academy of Sciences of the United States of America. 96 (6): 2794–9. Bibcode:1999PNAS...96.2794S. doi: 10.1073/pnas.96.6.2794 . PMC   15848 . PMID   10077590.
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  14. 1 2 3 4 Trockenbacher A, Suckow V, Foerster J, Winter J, Krauss S, Ropers HH, et al. (November 2001). "MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation". Nature Genetics. 29 (3): 287–94. doi:10.1038/ng762. PMID   11685209. S2CID   34834612.
  15. ↑ Han X, Du H, Massiah MA (April 2011). "Detection and characterization of the in vitro e3 ligase activity of the human MID1 protein". Journal of Molecular Biology. 407 (4): 505–20. doi:10.1016/j.jmb.2011.01.048. PMID   21296087.
  16. ↑ Napolitano LM, Jaffray EG, Hay RT, Meroni G (March 2011). "Functional interactions between ubiquitin E2 enzymes and TRIM proteins" (PDF). The Biochemical Journal. 434 (2): 309–19. doi:10.1042/BJ20101487. PMID   21143188. S2CID   5932399.
  17. 1 2 3 Schweiger S, Dorn S, Fuchs M, Köhler A, Matthes F, Müller EC, et al. (November 2014). "The E3 ubiquitin ligase MID1 catalyzes ubiquitination and cleavage of Fu". The Journal of Biological Chemistry. 289 (46): 31805–17. doi: 10.1074/jbc.M113.541219 . PMC   4231658 . PMID   25278022.
  18. 1 2 3 Pfirrmann T, Jandt E, Ranft S, Lokapally A, Neuhaus H, Perron M, et al. (September 2016). "Hedgehog-dependent E3-ligase Midline1 regulates ubiquitin-mediated proteasomal degradation of Pax6 during visual system development". Proceedings of the National Academy of Sciences of the United States of America. 113 (36): 10103–8. Bibcode:2016PNAS..11310103P. doi: 10.1073/pnas.1600770113 . PMC   5018744 . PMID   27555585.
  19. ↑ Zanchetta ME, Napolitano LM, Maddalo D, Meroni G (October 2017). "The E3 ubiquitin ligase MID1/TRIM18 promotes atypical ubiquitination of the BRCA2-associated factor 35, BRAF35". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1864 (10): 1844–1854. doi:10.1016/j.bbamcr.2017.07.014. PMID   28760657.
  20. ↑ Watkins GR, Wang N, Mazalouskas MD, Gomez RJ, Guthrie CR, Kraemer BC, et al. (July 2012). "Monoubiquitination promotes calpain cleavage of the protein phosphatase 2A (PP2A) regulatory subunit α4, altering PP2A stability and microtubule-associated protein phosphorylation". The Journal of Biological Chemistry. 287 (29): 24207–15. doi: 10.1074/jbc.M112.368613 . PMC   3397847 . PMID   22613722.
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  22. ↑ Liu E, Knutzen CA, Krauss S, Schweiger S, Chiang GG (May 2011). "Control of mTORC1 signaling by the Opitz syndrome protein MID1". Proceedings of the National Academy of Sciences of the United States of America. 108 (21): 8680–5. Bibcode:2011PNAS..108.8680L. doi: 10.1073/pnas.1100131108 . PMC   3102420 . PMID   21555591.
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  24. ↑ Krauss S, Foerster J, Schneider R, Schweiger S (June 2008). "Protein phosphatase 2A and rapamycin regulate the nuclear localization and activity of the transcription factor GLI3". Cancer Research. 68 (12): 4658–65. doi: 10.1158/0008-5472.CAN-07-6174 . PMID   18559511.
  25. ↑ Granata A, Quaderi NA (June 2003). "The Opitz syndrome gene MID1 is essential for establishing asymmetric gene expression in Hensen's node". Developmental Biology. 258 (2): 397–405. doi:10.1016/s0012-1606(03)00131-3. PMID   12798296.
  26. ↑ Dal Zotto L, Quaderi NA, Elliott R, Lingerfelter PA, Carrel L, Valsecchi V, et al. (March 1998). "The mouse Mid1 gene: implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region". Human Molecular Genetics. 7 (3): 489–99. doi: 10.1093/hmg/7.3.489 . PMID   9467009.
  27. ↑ Lancioni A, Pizzo M, Fontanella B, Ferrentino R, Napolitano LM, De Leonibus E, et al. (February 2010). "Lack of Mid1, the mouse ortholog of the Opitz syndrome gene, causes abnormal development of the anterior cerebellar vermis". The Journal of Neuroscience. 30 (8): 2880–7. doi:10.1523/JNEUROSCI.4196-09.2010. PMC   6633954 . PMID   20181585.
  28. ↑ Richman JM, Fu KK, Cox LL, Sibbons JP, Cox TC (2002). "Isolation and characterisation of the chick orthologue of the Opitz syndrome gene, Mid1, supports a conserved role in vertebrate development". The International Journal of Developmental Biology. 46 (4): 441–8. PMID   12141430.
  29. ↑ Latta EJ, Golding JP (2011). "Regulation of PP2A activity by Mid1 controls cranial neural crest speed and gangliogenesis". Mechanisms of Development. 128 (11–12): 560–76. doi: 10.1016/j.mod.2012.01.002 . PMID   22285438.
  30. ↑ Suzuki M, Hara Y, Takagi C, Yamamoto TS, Ueno N (July 2010). "MID1 and MID2 are required for Xenopus neural tube closure through the regulation of microtubule organization". Development. 137 (14): 2329–39. doi: 10.1242/dev.048769 . PMID   20534674.
  31. ↑ Pinson L, Augé J, Audollent S, Mattéi G, Etchevers H, Gigarel N, et al. (May 2004). "Embryonic expression of the human MID1 gene and its mutations in Opitz syndrome". Journal of Medical Genetics. 41 (5): 381–6. doi:10.1136/jmg.2003.014829. PMC   1735763 . PMID   15121778.
  32. 1 2 3 Fontanella B, Russolillo G, Meroni G (May 2008). "MID1 mutations in patients with X-linked Opitz G/BBB syndrome". Human Mutation. 29 (5): 584–94. doi: 10.1002/humu.20706 . PMID   18360914.

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