MID2 explained

Midline-2 is a protein that in humans is encoded by the MID2 gene.^{[1] [2]}

Function

The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein localizes to microtubular structures in the cytoplasm. Its function has not been identified. Alternate splicing of this gene results in two transcript variants encoding different isoforms.^[2]

Recent reports indicate the involvement of MID2 in cytokinesis ^{[3] [4]} .MID2 (TRIM1) ubiquitinates Sperm-associated antigen 5 (Astrin) on K409, further promoting its degradation and proper cytokinesis. In contrary, depletion of MID2 (TRIM1) stabilizes Sperm-associated antigen 5 (Astrin) whose inappropriate accumulation at the midbody triggers cytokinetic arrest, multinucleated cells, and cell death.

Interactions

MID2 has been shown to interact with MID1.^{[5] [6]}

MID2 (TRIM1) interacts with Leucine-rich repeat kinase 2 (LRRK2), which is often subject to missense mutations in familial Parkinson's disease (PD).^[7] MID2 (TRIM1) specifically binds to the flexible regulatory loop of LRRK2_853–981. MID2 (TRIM1) recruits LRRK2 to the microtubule cytoskeleton where MID2 (TRIM1) ubiquitinates LRRK2 targeting it for proteasomal degradation.

Further reading

• Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY . 6 . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration . Cell . 125 . 4 . 801–814 . May 2006 . 16713569 . 10.1016/j.cell.2006.03.032 . Huda Zoghbi . free .
• Jehee FS, Rosenberg C, Krepischi-Santos AC, Kok F, Knijnenburg J, Froyen G, Vianna-Morgante AM, Opitz JM, Passos-Bueno MR . 6 . An Xq22.3 duplication detected by comparative genomic hybridization microarray (Array-CGH) defines a new locus (FGS5) for FG syndrome . American Journal of Medical Genetics. Part A . 139 . 3 . 221–226 . December 2005 . 16283679 . 10.1002/ajmg.a.30991 . 37197250 .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . 6 . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–1178 . October 2005 . 16189514 . 10.1038/nature04209 . 4427026 . 2005Natur.437.1173R .
• Yap MW, Nisole S, Lynch C, Stoye JP . Trim5alpha protein restricts both HIV-1 and murine leukemia virus . Proceedings of the National Academy of Sciences of the United States of America . 101 . 29 . 10786–10791 . July 2004 . 15249690 . 490012 . 10.1073/pnas.0402876101 . free . 2004PNAS..10110786Y .
• Short KM, Hopwood B, Yi Z, Cox TC . 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 . BMC Cell Biology . 3 . 1 . 2002 . 11806752 . 64779 . 10.1186/1471-2121-3-1 . free .
• Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A . 6 . The tripartite motif family identifies cell compartments . The EMBO Journal . 20 . 9 . 2140–2151 . May 2001 . 11331580 . 125245 . 10.1093/emboj/20.9.2140 .
• Perry J, Short KM, Romer JT, Swift S, Cox TC, Ashworth A . FXY2/MID2, a gene related to the X-linked Opitz syndrome gene FXY/MID1, maps to Xq22 and encodes a FNIII domain-containing protein that associates with microtubules . Genomics . 62 . 3 . 385–394 . December 1999 . 10644436 . 10.1006/geno.1999.6043 .
• Cainarca S, Messali S, Ballabio A, Meroni G . Functional characterization of the Opitz syndrome gene product (midin): evidence for homodimerization and association with microtubules throughout the cell cycle . Human Molecular Genetics . 8 . 8 . 1387–1396 . August 1999 . 10400985 . 10.1093/hmg/8.8.1387 . free .

Notes and References

1. Buchner G, Montini E, Andolfi G, Quaderi N, Cainarca S, Messali S, Bassi MT, Ballabio A, Meroni G, Franco B . 6 . MID2, a homologue of the Opitz syndrome gene MID1: similarities in subcellular localization and differences in expression during development . Human Molecular Genetics . 8 . 8 . 1397–1407 . August 1999 . 10400986 . 10.1093/hmg/8.8.1397 . free .
2. Web site: Entrez Gene: MID2 midline 2.
3. Zanchetta ME, Meroni G . Emerging Roles of the TRIM E3 Ubiquitin Ligases MID1 and MID2 in Cytokinesis . Frontiers in Physiology . 10 . 274 . 2019-03-19 . 30941058 . 6433704 . 10.3389/fphys.2019.00274 . free .
4. Gholkar AA, Senese S, Lo YC, Vides E, Contreras E, Hodara E, Capri J, Whitelegge JP, Torres JZ . 6 . The X-Linked-Intellectual-Disability-Associated Ubiquitin Ligase Mid2 Interacts with Astrin and Regulates Astrin Levels to Promote Cell Division . Cell Reports . 14 . 2 . 180–188 . January 2016 . 26748699 . 4724641 . 10.1016/j.celrep.2015.12.035 .
5. Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A . 6 . The tripartite motif family identifies cell compartments . The EMBO Journal . 20 . 9 . 2140–2151 . May 2001 . 11331580 . 125245 . 10.1093/emboj/20.9.2140 .
6. Short KM, Hopwood B, Yi Z, Cox TC . 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 . BMC Cell Biology . 3 . 1 . 2002 . 11806752 . 64779 . 10.1186/1471-2121-3-1 . free .
7. Stormo AE, Shavarebi F, FitzGibbon M, Earley EM, Ahrendt H, Lum LS, Verschueren E, Swaney DL, Skibinski G, Ravisankar A, van Haren J, Davis EJ, Johnson JR, Von Dollen J, Balen C, Porath J, Crosio C, Mirescu C, Iaccarino C, Dauer WT, Nichols RJ, Wittmann T, Cox TC, Finkbeiner S, Krogan NJ, Oakes SA, Hiniker A . 6 . The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity . The Journal of Cell Biology . 221 . 4 . e202010065 . April 2022 . 35266954 . 8919618 . 10.1083/jcb.202010065 .