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MROH9

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MROH9 protein isoform 1 tertiary structure as found from I-Tasser and visualized with the NCBI iCN 3D Structure tool.

Maestro heat-like repeat-containing protein family member 9 (MROH9) is a protein which in humans is encoded by the MROH9 gene[1]. The word ‘maestro’ itself is an acronym, standing for male-specific transcription in the developing reproductive organs (MRO). MRO genes belong to the MROH family, which includes MROH9[2].

Gene

MROH9 is also known as C1orf129 and ARMC11(armadillo repeat-containing 11)[3] [4]. The genomic location is on chromosome 1 (1q24.3) on its plus end, spanning 129,232 base pairs.

MROH9 genomic location on chromosome 1[3].

Transcript

The MROH9 gene is encoded by an mRNA transcript that is 3,102 nucleotides in length. mRNA transcript variant 1 (NM_001163629.2), which encodes protein isoform 1 (NP_001157101.1), is the longest transcript encoding the longest, highest-quality isoform[1]. Transcript variant 2 is found to have a shorter, more distant C-terminus, and an alternative 3’ coding region and 3’ UTR compared to variant 1. Transcript variant 1 has 23 exons, making up a coding sequence that is 2,586 nucleotides long[1].

Middle region of an annotated conceptual translation for the MROH9 protein sequence and nucleotide transcript. Annotations show HEAT regions, alpha helices, exon boundaries, well-conserved amino acids (in bold), and eukaryotic linear motifs (ELMs)[1][5].

Protein

The dominant isoform protein that the MROH9 encodes is isoform 1, with a length of 861 amino acids[3]. Table 1 displays some of the other common protein isoforms of the MROH9.

Isoform Accession number Length (a.a.) Exons Domains
1 NP_001157101.1 861 23 5 HEATs, 2 HEAT repeats
2 NP_079339.2 573 15 5 HEATs
                  X1 XP_011508307.1 811 21 3 HEAT repeats
                  X2 XP_011508308.1 803 20 none
                  X3 XP_011508309.1 546 12 3 HEAT repeats

Table 1: Information about the different isoforms of the MROH9 gene

The isoforms of the MROH9 gene and their respective lengths and exon numbers[3][6].

Domains

Of the 11 MROH genes in the family, all of their respective proteins contain HEAT repeats, a type of protein structural motif made up of a short loop linking two alpha helices. HEAT repeats, structurally related to armadillo repeats, are known to form superhelical structures involved in intracellular transport[2]. Protein isoform 1 encoded by the MROH9 gene has 5 HEAT regions and 2 HEAT repeats; the quantity of these vary across the different isoforms, as seen in the table[7].

Structure

A multiple sequence alignment of strict orthologs of the MROH9 gene in other mammalian taxons, showing the protein sequence from amino acids 39-391 in humans[8].

The secondary structure of human MROH9 protein isoform 1 has 49 alpha helices with no apparent sheets or coils[1]. The I-TASSER result displaying the tertiary structure with the highest probability score is pictured at the top of the page, and this structure was seen across orthologs, as well[9].

Regulation

Gene Level

Heightened localized expression of the MROH9 gene found in the olfactory bulb region of the mouse brain[10].

The encoded transcript of MRO genes were found in one study to exhibit “sexual dimorphic expression during murine gonadal development.” The researchers also found increased expression of MRO genes in human testicular tissue, and a particular cytoplasmic expression pattern of the protein in testicular germ cells[2].

RNAseq data from NCBI Gene shows that MROH9 in humans is only consistently expressed in the lungs and no other tissue, though it shows notable expression in the intestines, stomach, and male/female gonads in almost all of the sets[3]. Low probability scores imply that this gene might be expressed at very low levels. Microarray-assessed tissue expression pattern data from confirms that expression is higher in the lungs, though very low across all other various tissues. Conditional expression pattern data shows that MROH9 is not particularly expressed in any one condition over the other[3].

The Allen Mouse Brain Atlas confirm the gene’s expression in lung, intestine, and gonad tissue. MROH9 expression specifically correlates with a cluster that specializes in cilium organization and cilia cells. The Allen Mouse Brain Atlas also shows that the gene shows significant levels of expression in the olfactory bulb region of the brain. Since the lung, gonads, intestines, and nose all require cilia cells to function, it is possible that the MROH9 gene confers the function of such tissues[10].

Cartoon visualizing important domains and sites on the MROH9 protein, including HEAT repeat regions and predicted phosphorylation sites.

Protein Level

Subcellular localization of the MROH9 isoform 1 protein is predicted to be within the cytoplasm[11]. This is consistent across strict and distant orthologs, too, as the MROH9 protein shows cytoplasmic subcellular localization across most mammalian taxons. However, predicted data report that the protein could be important in the mitochondria, endoplasmic reticulum, and Golgi apparatus[11].

Predicted post-translational modifications reported by MyHits Motif Scan show that the MROH9 protein may have 27 phosphorylation sites, 7 N-linked glycosylation sites, and 4 myristoylation sites. However, considering that the probability scores are very low and that this protein is most probably located in the cytoplasm - meaning that it does not travel across membranes - predicted N-linked glycosylation and myristoylation sites are likely null. Phosphorylation is the only likely modification that can occur for this protein, but only a small handful of the predicted sites are conserved across MROH9 orthologs. Other phosphorylation sites, along with all the predicted N-linked glycosylation and myristoylation sites, are quite poorly conserved across orthologs[12]. Predicted eukaryotic linear motifs (ELMs) show several matched sequences for cleavage sites, implying that the MROH9 protein sequence might be cleaved as part of its function[5].

Evolution

Scientific name Common name Taxon median date of divergence (MYA) Accession # Length (amino acids) % identity to humans % similarity to humans
Homo sapiens Human Primates 0 NP_001157101.1 861 100% 100%
Chlorocebus sabaeus Green monkey Primates 29 XP_037842145.1 891 87% 92%
Ochotona curzoniae Black-lipped pika Glires 87 XP_040842726.1 921 63% 77%
Mus musculus House mouse Glires 87 NP_084347.1 891 59% 76%
Balenoptera musculus Blue whale Artiodactyla 94 XP_036729523.1 912 70% 82%
Sus scrofa Wild pig Artiodactyla 94 XP_020919615.1 912 70% 81%
Hyaena hyaena Striped hyena Carnivora 94 XP_039077615.1 858 68% 81%
Condylura cristata Star-nosed mole Eulipotyphla 94 XP_004688175.1 1007 64% 80%
Rhinolophus ferrumequinum Greater horseshoe bat Chiroptera 94 XP_032948567.1 884 65% 79%
Equus asinus Ass Perissodactyla 94 XP_044614605.1 901 63% 75%
Loxodonta africana African savanna elephant Afrotheria 99 XP_010593357.1 907 65% 79%
Choloepus didactylus Southern two-toed sloth Xenarthra 99 XP_037662834.1 855 64% 78%
Vombatus ursinus Common wombat Marsupialia 160 XP_027724161.1 857 50% 67%
Antechinus flavipes Yellow-footed antechinus Marsupialia 160 XP_051854920.1 798 51% 70%

Table 2: MROH9 orthologs and related properties

Orthologs of the human MROH9 gene (NP_001157101.1) in various animals across mammalian taxon groups[3][13]. MYA refers to how many million years ago the mammalian taxon diverged from the human species.

Interestingly, MROH9 orthologs were observed to only be found in mammalian species, as seen in the table above. Absolutely no homologs or orthologs were found in any birds, reptiles, amphibians, invertebrates, fungi, plants, or bacteria. Orthologs could be found in every extant mammalian species with the exception of Monotremes, which only showed homologs for different isoforms and various paralogs. It also appears that there is no direct correlation between estimated date of divergence and sequence similarity with humans; orthologs found in animals in the Glires taxon (which diverged most recently in mammals) showed less similarity to the human MROH9 sequence compared to mammal groups that diverged longer ago[3].

Paralog

Scientific name Common name Taxon median date of divergence (MYA) Accession # Length (amino acids) % identity to humans % similarity to humans
Homo sapiens Human Primates 0 KAI2517273.1 898 100% 100%
Ochotona curzoniae Black-lipped pika Glires 87 XP_040834542.1 1311 87% 92%
Hyaena hyaena Striped hyena Carnivora 94 XP_039095139.1 1319 87% 92%
Equus asinus Ass Perissodactyla 94 XP_014699852.1 1325 87% 93%

Table 3: Orthologs of MROH7 and related properties

Orthologs of the human MROH7 gene (KAI2517273.1), a paralog to MROH9, in various animals across mammalian taxon groups that had the ortholog[3][13]. MYA refers to how many million years ago the mammalian taxon diverged from the human species.


MROH7 is a notable paralog of the MROH9 gene and is found in humans as well as some other select mammal species. The second table above shows some of these paralogs and their sequence identity and similarity to the human MROH7 gene. Human MROH7 was found to have a 22% shared sequence identity to the human MROH9 gene[3].

Graph plotting the corrected sequence divergence and median date of divergence for MROH9, MROH7, cytochrome C, and fibrinogen alpha in humans and orthologous species.

The graph to the right shows the corrected sequence divergence versus median date of divergence of MROH9. Plotted with the rate of evolution of MROH9 are rates for fibrinogen alpha (a rapidly evolving gene), cytochrome C (a slowly evolving gene), and the MROH7 paralog[14][15]. The graph shows that the slope for MROH7 evolution is much lower than MROH9, with its rate of divergence being almost similar to that of cytochrome C. All of the orthologs of the MROH7 gene show the same sequence identity despite having diverged at different times in history. This could imply that the orthologs for the MROH7 gene are closer related together, and might have diverged from MROH9 roughly 94 million years ago and did not evolve much since then. It is also possible that the MROH7 paralog is evolving slower than the MROH9 gene[16].

Interacting Proteins

Both GLO1 and RNF123 appear in several databases and articles, heightening the possibility of these being genuine interacting proteins for MROH9[17][18]. RNF123 and PARK2, another interacting protein, are both E3 Ubiquitin ligases, which are responsible for targeting proteins for degradation[19]. GLO1, or lactoylglutathione ligase, is an enzyme catalyzing isomerization of hemithioacetal adducts[20]. These results explain that MROH9 function may depend on the activity of these ligases and might be degraded.

Clinical Significance

MROH9 appears in several publications indicating its potential role as an oncogene in various types of cancers. One paper found that there was excessive chromatin looping near MROH9 and several FMO genes (gene neighbors to MROH9 on chromosome 1), along with other key oncogenes in nasopharyngeal cancer, potentially linking MROH9 with oncogene properties[21][22]. MROH9 has also been found to play roles as an oncogene in other forms of cancer; studies have found it to be a potential necroptosis-related gene that is overexpressed in high-risk groups for pancreatic adenocarcinoma[23][24]. MROH9 has been further confirmed by some studies as an oncogene for breast cancers, with alterations in chromosome 1 being described in over half of breast cancer tumors. A large number of copy number variations (CNVs) are particularly found on the 1q arm of chromosome 1 where MROH9 is found[25]. Other research found MROH9 to be a predicted target of miR-3646, a type of microRNA that promotes cell proliferation in human breast cancer cells[26]. In addition to this, MROH9 is also found at a chromosome 1 locus that is associated with central corneal thickness, a measure of glaucoma. It is found at the associated locus together with PRRX1, another gene that, along with MROH9, was also found to be an associated variant in systemic lupus erythematosus[27][28].

References

  1. ^ a b c d e NCBI (National Center for Biotechnology Information) entry on maestro heat-like repeat-containing protein family member 9 isoform 1 [Homo sapiens] https://www.ncbi.nlm.nih.gov/protein/254692913
  2. ^ a b c Kenigsberg, Shlomit; Lima, Patricia D. A.; Maghen, Leila; Wyse, Brandon A.; Lackan, Chantal; Cheung, Annie N. Y.; Tsang, Benjamin K.; Librach, Clifford L. (2017-04-13). "The elusive MAESTRO gene: Its human reproductive tissue-specific expression pattern". PLOS ONE. 12 (4): e0174873. doi:10.1371/journal.pone.0174873. ISSN 1932-6203. PMC 5391009. PMID 28406912.
  3. ^ a b c d e f g h i j NCBI (National Center for Biotechnology Information) entry on Homo sapiens MROH9 gene https://www.ncbi.nlm.nih.gov/gene/80133
  4. ^ GeneCards entry on MROH9 gene https://www.genecards.org/cgi-bin/carddisp.pl?gene=MROH9
  5. ^ a b "ELM - Search the ELM resource". elm.eu.org. Retrieved 2022-12-16.
  6. ^ "Human BLAT Search". genome.ucsc.edu. Retrieved 2022-12-16.
  7. ^ "HEAT repeat", Wikipedia, 2022-11-20, retrieved 2022-12-16
  8. ^ "Clustal Omega < Multiple Sequence Alignment < EMBL-EBI". www.ebi.ac.uk. Retrieved 2022-12-16.
  9. ^ "I-TASSER results". seq2fun.dcmb.med.umich.edu. Retrieved 2022-12-16.
  10. ^ a b "Gene Detail :: Allen Brain Atlas: Mouse Brain". mouse.brain-map.org. Retrieved 2022-12-16.
  11. ^ a b "PSORT II Prediction". psort.hgc.jp. Retrieved 2022-12-16.
  12. ^ "Motif Scan". myhits.sib.swiss. Retrieved 2022-12-16.
  13. ^ a b "TimeTree :: The Timescale of Life". www.timetree.org. Retrieved 2022-12-16.
  14. ^ Kant, J A; Fornace, A J; Saxe, D; Simon, M I; McBride, O W; Crabtree, G R (1985-04-01). "Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion". Proceedings of the National Academy of Sciences. 82 (8): 2344–2348. doi:10.1073/pnas.82.8.2344. ISSN 0027-8424. PMC 397554. PMID 2986113.
  15. ^ Dickerson, Richard E. (1971-03-01). "The structure of cytochromec and the rates of molecular evolution". Journal of Molecular Evolution. 1 (1): 26–45. doi:10.1007/BF01659392. ISSN 1432-1432. PMID 4377446. S2CID 24992347.
  16. ^ "MROH7 maestro heat like repeat family member 7 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-16.
  17. ^ Huttlin, Edward L.; Bruckner, Raphael J.; Navarrete-Perea, Jose; Cannon, Joe R.; Baltier, Kurt; Gebreab, Fana; Gygi, Melanie P.; Thornock, Alexandra; Zarraga, Gabriela; Tam, Stanley; Szpyt, John; Gassaway, Brandon M.; Panov, Alexandra; Parzen, Hannah; Fu, Sipei (2021-05-27). "Dual proteome-scale networks reveal cell-specific remodeling of the human interactome". Cell. 184 (11): 3022–3040.e28. doi:10.1016/j.cell.2021.04.011. ISSN 0092-8674. PMC 8165030. PMID 33961781.
  18. ^ Khanna, Richa; Krishnamoorthy, Vidhya; Parnaik, Veena K. (2018-04-20). "E3 ubiquitin ligase RNF 123 targets lamin B1 and lamin‐binding proteins". The FEBS Journal. 285 (12): 2243–2262. doi:10.1111/febs.14477. ISSN 1742-464X. PMID 29676528. S2CID 4997525.
  19. ^ Sun, Xin; Shu, Yuhan; Ye, Guiqin; Wu, Caixia; Xu, Mengting; Gao, Ruilan; Huang, Dongsheng; Zhang, Jianbin (2022-02-01). "Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy". Acta Pharmaceutica Sinica B. 12 (2): 838–852. doi:10.1016/j.apsb.2021.07.003. ISSN 2211-3835. PMC 8897022. PMID 35256949.
  20. ^ "GLO1 Gene - GeneCards | LGUL Protein | LGUL Antibody". www.genecards.org. Retrieved 2022-12-16.
  21. ^ Animesh, Sambhavi; Choudhary, Ruchi; Wong, Bertrand Jern Han; Koh, Charlotte Tze Jia; Ng, Xin Yi; Tay, Joshua Kai Xun; Chong, Wan-Qin; Jian, Han; Chen, Leilei; Goh, Boon Cher; Fullwood, Melissa Jane (2021). "Profiling of 3D Genome Organization in Nasopharyngeal Cancer Needle Biopsy Patient Samples by a Modified Hi-C Approach". Frontiers in Genetics. 12: 673530. doi:10.3389/fgene.2021.673530. ISSN 1664-8021. PMC 8446523. PMID 34539729.
  22. ^ Uno, Yasuhiro; Shimizu, Makiko; Yamazaki, Hiroshi (2013-06-15). "Molecular and functional characterization of flavin-containing monooxygenases in cynomolgus macaque". Biochemical Pharmacology. 85 (12): 1837–1847. doi:10.1016/j.bcp.2013.04.012. ISSN 0006-2952. PMID 23623750.
  23. ^ Wu, Zixuan; Huang, Xuyan; Cai, Minjie; Huang, Peidong; Guan, Zunhui (2022-01-24). "Novel necroptosis-related gene signature for predicting the prognosis of pancreatic adenocarcinoma". Aging. 14 (2): 869–891. doi:10.18632/aging.203846. ISSN 1945-4589. PMC 8833111. PMID 35077391.
  24. ^ Lu, Juan; Yu, Chengbo; Bao, Qiongling; Zhang, Xiaoqian; Wang, Jie (2022). "Identification and analysis of necroptosis-associated signatures for prognostic and immune microenvironment evaluation in hepatocellular carcinoma". Frontiers in Immunology. 13: 973649. doi:10.3389/fimmu.2022.973649. ISSN 1664-3224. PMC 9445885. PMID 36081504.
  25. ^ Rodrigues‐Peres, Raquel M.; Carvalho, Benilton; Anurag, Meenakshi; Lei, Jonathan T.; Conz, Livia; Gonçalves, Rodrigo; Cardoso Filho, Cássio; Ramalho, Susana; Paiva, Geisilene R.; Derchain, Sophie F. M.; Lopes‐Cendes, Iscia; Ellis, Matthew J.; Sarian, Luis O. (2019-05-16). "Copy number alterations associated with clinical features in an underrepresented population with breast cancer". Molecular Genetics & Genomic Medicine. 7 (7): e00750. doi:10.1002/mgg3.750. ISSN 2324-9269. PMC 6625096. PMID 31099189.
  26. ^ Tao, Shuang; Liu, Yao-Bang; Zhou, Zhi-Wei; Lian, Bin; Li, Hong; Li, Jin-Ping; Zhou, Shu-Feng (2016-04-15). "miR-3646 promotes cell proliferation, migration, and invasion via regulating G2/M transition in human breast cancer cells". American Journal of Translational Research. 8 (4): 1659–1677. ISSN 1943-8141. PMC 4859896. PMID 27186291.
  27. ^ Choquet, Hélène; Melles, Ronald B.; Yin, Jie; Hoffmann, Thomas J.; Thai, Khanh K.; Kvale, Mark N.; Banda, Yambazi; Hardcastle, Alison J.; Tuft, Stephen J.; Glymour, M. Maria; Schaefer, Catherine; Risch, Neil; Nair, K. Saidas; Hysi, Pirro G.; Jorgenson, Eric (2020-06-11). "A multiethnic genome-wide analysis of 44,039 individuals identifies 41 new loci associated with central corneal thickness". Communications Biology. 3 (1): 301. doi:10.1038/s42003-020-1037-7. ISSN 2399-3642. PMC 7289804. PMID 32528159.
  28. ^ Wang, Yong-Fei; Zhang, Yan; Lin, Zhiming; Zhang, Huoru; Wang, Ting-You; Cao, Yujie; Morris, David L.; Sheng, Yujun; Yin, Xianyong; Zhong, Shi-Long; Gu, Xiaoqiong; Lei, Yao; He, Jing; Wu, Qi; Shen, Jiangshan Jane (2021-02-03). "Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups". Nature Communications. 12 (1): 772. doi:10.1038/s41467-021-21049-y. ISSN 2041-1723. PMC 7858632. PMID 33536424.
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