Biology:ARMH3

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

ARMH3 or Armadillo Like Helical Domain Containing 3, also known as UPF0668 and c10orf76, is a protein that in humans is encoded by the ARMH3 gene.[1] Its function is not currently known, but experimental evidence has suggested that it may be involved in transcriptional regulation.[2] The protein contains a conserved proline-rich motif,[1][3] suggesting that it may participate in protein-protein interactions via an SH3-binding domain,[4] although no such interactions have been experimentally verified. The well-conserved gene appears to have emerged in Fungi approximately 1.2 billion years ago.[3][5] The locus is alternatively spliced and predicted to yield five protein variants, three of which contain a protein domain of unknown function, DUF1741.[1][6]

Function

It has been found to contain a potential SH3-binding domain,[1][4] which is known to participate in protein-protein binding interactions; however, no protein interactions have been experimentally verified with c10orf76. A 2007 gene expression study found c10orf76 expression to vary inversely with the expression of several other genes, including NFYB, CCR5, and NSBP1, suggesting that the protein may function as a transcriptional regulator.[2]

Homology

ARMH3 is well-conserved throughout Eumetazoans.[1][3] Some weakly similar orthologs (approximately 35% sequence identity) were identified in Parazoa (i.e., A. queenslandica) and in Fungi, specifically Ascomycetes (i.e., A. oryzae).[3]

The following table illustrates the sequence similarity between human c10orf76 protein and various orthologs. Similar sequences were identified with BLAST[3] and BLAT[7] tools.

Species Organism Common Name NCBI Accession Sequence Identity Sequence Similarity Length (AAs) Gene Common Name
Homo sapiens Human NP_078817.2 100% 100% 689 UPF0668 protein C10orf76
Mus musculus House Mouse NP_938038.2 99% 99% 689 UPF0668 protein C10orf76 homolog
Danio rerio Zebrafish NP_956913.2 85% 93% 689 UPF0668 protein C10orf76 homolog
Apis florea Honey bee XP_003695991.1 51% 70% 641 PREDICTED: UPF0668 protein C10orf76 homolog
Amphimedon queenslandica Sponge XP_003383350.1 46% 67% 667 PREDICTED: UPF0668 protein C10orf76-like
Acyrthosiphon pisum Pea Aphid XP_001952575.2 40% 61% 684 PREDICTED: UPF0668 protein C10orf76 homolog isoform 1
Aspergillus oryzae Fungus XP_001820240 23% 42% 653 hypothetical protein AOR_1_2042154

Gene

Characteristics

In humans, the ARMH3 gene, also known by the alias FLJ13114, spans 210,577 base pairs on the reverse strand of the long arm of chromosome 10.[6] Its 26 alternatively spliced exons encode 5 potential transcript variants, the largest of which being 4101 base pairs in length.[6]

A map of human chromosome 10 with c10orf76 marked with the red line.

The human ARMH3 locus is flanked on the left and right sides by HPS6 and KCNIP2, respectively.[1] HPS6 is a protein that may play a role in organelle biogenesis,[8] and KCNIP2 is a voltage-gated potassium channel interacting protein.[9] The same pattern is observed in the orthologous locus in mice,[10] as well as most other vertebrates.

Expression

The NCBI (GenBank) gene profile for c10orf76 labels the start of the first transcribed exon as the beginning of the gene.[1] The primary promoter predicted by the El Dorado tool from Genomatix begins 519 base pairs upstream of this transcription start site.[11] This promoter is predicted to be 658 base pairs in length and thus includes the first transcribed exon at its 3 prime end.[1]

The c10orf76 locus is thought to be alternatively spliced into at least five unique isoforms, although it is unclear how this splicing is regulated.[1] A second potential promoter, also predicted by El Dorado, likely drives expression of one of the shorter documented variants (positioned before exon 23).[6][11]

Protein

Characteristics

The largest protein variant is 689 amino acids in length.[1] It has a molecular mass of approximately 78.7kDa and is isoelectric at pH 6.13.[12] It may be secreted via a non-classical pathway.[13] NCBI identifies a protein domain of unknown function between amino acids Asp435 and Leu671, known as DUF1741 (Domain of Unknown Function 1741).[1] This domain is not known to exist in any other proteins.[3]

Expression

A potential stem loop region at the 3 prime end of the first exon (and thus, the end of the promoter) was predicted by the Dotlet program from ExPASy.[14] This could serve to regulate protein translation.[15] Also, an Alu segment in the 3 prime untranslated region of the mature mRNA could serve as a potential translational regulatory mechanism.[16]

The protein has been found to be differentially expressed in some medical conditions and in response to certain cellular signals. For example, decreased c10orf76 expression is observed in patients with chronic B-cell lymphocytic leukemia.[17] Decreased expression is also observed in cells treated with vascular endothelial growth factor.[18]

The protein is thought to be localized to the cytoplasm,[19] although this is uncertain. It has also been predicted to be a 3-pass transmembrane protein.[12] Also, a mitochondrial sorting signal was identified at the beginning of one of the protein isoforms using MitoProt II (located at Met416 of the largest protein variant).[20]

Structure

A structural prediction of c10orf76 protein from PHYRE2 protein folding software. This structure is similar to that of human Symplekin, a protein thought to recruit regulatory factors to the polyadenylation machinery.[21]

The structure of the c10orf76 protein has not been experimentally explored. The secondary structure is predicted to be completely helical in nature, with intervening regions of protein disorder.[22][23] The potential SH3-binding domain is located on a predicted region of disorder, further supporting a protein-protein binding function for c10orf76. A helical region between amino acids 610-655 was predicted to be a coiled coil motif.[24]

A PHYRE2[25] protein structure prediction suggested that the first 200 residues of c10orf76 may share strong structural similarities with Symplekin,[22] a nuclear-localized protein that is thought to be a scaffold component of the polyadenylation complex.[21]

Predicted protein Interactions

The expression of c10orf76 mRNA has been found to be inversely correlated with expression of various other mRNAs, including NFYB, CCR5, and NSBP1.[2] Although this study and the predicted SH3-binding domain suggest that c10orf76 partakes in protein-protein binding interactions, none have been experimentally verified. A short search using IntAct,[26] MINT,[27] and STRING[28] also yielded zero predicted protein-protein interactions.

Predicted posttranslational modifications

There is a potential that the protein is secreted via a non-classical pathway,[13] which may underlie the functionality of some of the posttranslational modifications. There are ten conserved potential phosphorylation sites within the protein sequence.[29] Also, there are nine residues that are confidently (>90%) predicted by NetOGlyc[30] to undergo O-linked glycosylation, all residing within the low complexity region between Leu325 and Ser359.


Regions of potential research interest

The protein coded by the largest mRNA variant of c10orf76 encodes a proline-rich motif containing two PxxP domains, where "P" represents a proline residue and "x" represents any other amino acid[1] (highlighted in blue below). These domains have been shown to participate in protein-protein binding interactions, specifically via the SH3 protein binding domain.[4] The potential SH3-binding domain exists within a low complexity region with an unusually high number of amino acids with oxygen-containing side-groups (highlighted in green below). An NetOGlyc analysis[30] of the region suggests that these residues are likely to undergo O-linked glycosylation and thus may serve to regulate binding to the potential SH3-binding domain.[31]

325 L V T T P V S P A P T T P V T P L G T T P P S S 359

An Alu element was identified in the 3`-UTR of the longest mRNA transcript variant[1] It is unclear as to whether this sequence serves any functional or regulatory purpose, but there is existing evidence for Alu-mediated protein translation regulation, so this cannot be ruled out in c10orf76.[16]

The N-terminus of a short transcript variant (exons 17-26) was predicted to have a mitochondrial sorting signal with 96% confidence using the MitoProt II tool.[20] It is unclear as to whether this is a uniquely transcribed variant or it results from protein cleavage of the full-size protein. There are no predicted alternative promoters upstream of this variant's first exon.[11]

Model organisms

Model organisms have been used in the study of C10orf76 function. A conditional knockout mouse line called 9130011E15Riktm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[32] Male and female animals underwent a standardized phenotypic screen[33] to determine the effects of deletion.[34][35][36][37] Additional screens performed: - In-depth immunological phenotyping[38] - in-depth bone and cartilage phenotyping[39]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 "Entrez Gene: Chromosome 10 open reading frame 76 (Human)". https://www.ncbi.nlm.nih.gov/gene/79591. Retrieved 28 April 2013. 
  2. ↑ 2.0 2.1 2.2 "An RNA targeted to the HIV-1 LTR promoter modulates indiscriminate off-target gene activation". Nucleic Acids Research 35 (21): 7303–12. 2007. doi:10.1093/nar/gkm847. PMID 17959645. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "NCBI BLAST Tool". http://blast.ncbi.nlm.nih.gov/Blast.cgi. Retrieved 2 April 2013. 
  4. ↑ 4.0 4.1 4.2 "Novel Src homology 3 domain-binding motifs identified from proteomic screen of a Pro-rich region". Molecular & Cellular Proteomics 4 (8): 1155–66. Aug 2005. doi:10.1074/mcp.M500108-MCP200. PMID 15929943. 
  5. ↑ "TimeTree: The Timescale of Life". http://www.timetree.org/index.php?taxon_a=homo+sapiens&taxon_b=aspergillus+oryzae&submit=Search. Retrieved 23 May 2013. 
  6. ↑ 6.0 6.1 6.2 6.3 "AceView: c10orf76". https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&term=c10orf76&submit=Go. Retrieved 28 April 2013. 
  7. ↑ UCSC Genome Bioinformatics. "Human BLAT Search Tool". http://genome.ucsc.edu/cgi-bin/hgBlat?command=start. Retrieved 18 March 2013. 
  8. ↑ "Entrez Gene: HPS6 Hermansky-Pudlak syndrome 6". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=79803. Retrieved 5 May 2013. 
  9. ↑ "Neuronal calcium sensor proteins: generating diversity in neuronal Ca2+ signalling". Nature Reviews. Neuroscience 8 (3): 182–93. Mar 2007. doi:10.1038/nrn2093. PMID 17311005. 
  10. ↑ "Entrez Gene: 9130011E15Rik cDNA (Mus musculus)". https://www.ncbi.nlm.nih.gov/gene/?term=c10orf76+mus+musculus. Retrieved 13 May 2013. 
  11. ↑ 11.0 11.1 11.2 "El Dorado Gene Promoter Analysis". http://www.genomatix.de/online_help/help_eldorado/introduction.html. Retrieved 21 April 2013. 
  12. ↑ 12.0 12.1 SDSC Biology Workbench. "Biology WorkBench 3.2". http://workbench.sdsc.edu. Retrieved 1 May 2013. 
  13. ↑ 13.0 13.1 "SecretomeP". http://www.cbs.dtu.dk/services/SecretomeP/. Retrieved 18 April 2013. 
  14. ↑ "Sib Dotlet Sequence Alignment". http://myhits.isb-sib.ch/cgi-bin/dotlet. Retrieved 13 May 2013. 
  15. ↑ "The stem-loop structure at the 3' end of histone mRNA is necessary and sufficient for regulation of histone mRNA stability". Molecular and Cellular Biology 7 (12): 4557–9. Dec 1987. doi:10.1128/MCB.7.12.4557. PMID 3437896. 
  16. ↑ 16.0 16.1 "Alu elements as regulators of gene expression". Nucleic Acids Research 34 (19): 5491–7. 2006. doi:10.1093/nar/gkl706. PMID 17020921. 
  17. ↑ "Geo Profile: Differential Expression of c10orf76 in B-cell leukemia". https://www.ncbi.nlm.nih.gov/geoprofiles/72020876. Retrieved 13 May 2013. 
  18. ↑ "Geo Profile: Differential Expression of c10orf76 under VEGF-A conditions". https://www.ncbi.nlm.nih.gov/geoprofiles/61139955. Retrieved 13 May 2013. 
  19. ↑ "SOSUI Localization Prediction". http://bp.nuap.nagoya-u.ac.jp/sosui/cgi-bin/adv_sosui.cgi. Retrieved 24 April 2013. 
  20. ↑ 20.0 20.1 "MitoProt II - v1.101". http://ihg.gsf.de/cgi-bin/paolo/mitofilter?seq=MNFRVNLHRMPMRHRKKAADKNLPCRPLVCAVLDLMVEFIVTHMMKEFPMDLYIRCIQVVHKLLCYQKKCRVRLHYTWRELWSALINLLKFLMSNETVLLAKHNIFTLALMIVNLFNMFITYGDTFLPTPSSYDELYYEIIRMHQSFDNLYSMVLRLSTNAGQWKEAASKVTHALVNIRAIINHFNPKIESYAAVNHISQLSEEQVLEVVRANYDTLTLKLQDGLDQYERYSEQHKEAAFFKELVRSISTNVRRNLAFHTLSQEVLLKEFSTIS&seqname=. Retrieved 13 May 2013. 
  21. ↑ 21.0 21.1 "Complex protein interactions within the human polyadenylation machinery identify a novel component". Molecular and Cellular Biology 20 (5): 1515–25. Mar 2000. doi:10.1128/MCB.20.5.1515-1525.2000. PMID 10669729. 
  22. ↑ 22.0 22.1 "PHYRE2 results for c10orf76". http://www.sbg.bio.ic.ac.uk/phyre2/phyre2_output/3937ea6e93e8d65d/summary.html. Retrieved 18 April 2013. [yes|permanent dead link|dead link}}]
  23. ↑ "PredictProtein - Sequence Analysis, Structure and Function Prediction". http://www.predictprotein.org/. Retrieved 18 April 2013. 
  24. ↑ "Predicting coiled coils from protein sequences". Science 252 (5009): 1162–4. May 1991. doi:10.1126/science.252.5009.1162. PMID 2031185. 
  25. ↑ "PHYRE2 Protein Fold Recognition Server". http://www.sbg.bio.ic.ac.uk/phyre2/html/page.cgi?id=index. Retrieved 18 April 2013. 
  26. ↑ "IntAct Interaction Database". http://www.ebi.ac.uk/intact/. Retrieved 3 May 2013. 
  27. ↑ "MINT: the Molecular INTeraction database". Nucleic Acids Research 35 (Database issue): D572–4. Jan 2007. doi:10.1093/nar/gkl950. PMID 17135203. 
  28. ↑ "STRING functional and predicted protein interactions". http://string-db.org/. Retrieved 10 May 2013. 
  29. ↑ "NetPhos". http://www.cbs.dtu.dk/services/NetPhos/. Retrieved 24 Apr 2013. 
  30. ↑ 30.0 30.1 "NetOGlyc". http://www.cbs.dtu.dk/services/NetOGlyc/. Retrieved 23 April 2013. 
  31. ↑ "Glycosylation of nucleocytoplasmic proteins: signal transduction and O-GlcNAc". Science 291 (5512): 2376–8. Mar 2001. doi:10.1126/science.1058714. PMID 11269319. 
  32. ↑ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. 
  33. ↑ 33.0 33.1 "International Mouse Phenotyping Consortium". http://www.mousephenotype.org/data/search?q=9130011E15Rik#fq=*:*&facet=gene. 
  34. ↑ "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. Jun 2011. doi:10.1038/nature10163. PMID 21677750. 
  35. ↑ "Mouse library set to be knockout". Nature 474 (7351): 262–3. Jun 2011. doi:10.1038/474262a. PMID 21677718. 
  36. ↑ "A mouse for all reasons". Cell 128 (1): 9–13. Jan 2007. doi:10.1016/j.cell.2006.12.018. PMID 17218247. 
  37. ↑ "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell 154 (2): 452–64. Jul 2013. doi:10.1016/j.cell.2013.06.022. PMID 23870131. 
  38. ↑ 38.0 38.1 "Infection and Immunity Immunophenotyping (3i) Consortium". http://www.immunophenotyping.org/data/search?keys=9130011E15Rik&field_gene_construct_tid=All. 
  39. ↑ "OBCD Consortium". http://www.boneandcartilage.com/. 

External links




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