IFFO1

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Wikidata
View/Edit Human

Intermediate filament family orphan 1 is a protein that in humans is encoded by the IFFO1 gene. IFFO1 has uncharacterized function and a weight of 61.98 kDa.[1] IFFO1 proteins play an important role in the cytoskeleton and the nuclear envelope of most eukaryotic cell types.[2]

Gene

IFFO in human is located on the minus strand at Chromosome 12p13.3. The protein contains 17,709 nucleotide bases that encodes for 570 amino acids. The basal isoelectric point is 4.83.[3] IFFO1 contains a highly conserved filament domain that spans 299 amino acids from amino residue 230 to 529.[4] This region has been identified as pfam00038 conserved protein domain family.[5] Due to alternative splicing, there are 7 isoforms of IFFO1 in humans with 10 typical coding exons.

File:Map of Chromosome 12.png
IFFO1 locus on Chromosome 12p13.3

Aliases

IFFO1 is also called Intermediate Filament Family Orphan Isoform X1, Intermediate Filament Family Orphan, HOM-TES-103, Intermediate Filament-Like MGC: 2625, and Tumor Antigen HOM-TES-10.[6]

Homology

Orthologs

The gene is found to be highly conserved. The most distant orthologs are found in fish and sharks (cartilaginous fishes) such as Callorhinchus milii.[7] Very low percentages of sequence coverage and identity of the gene's orthologs in fungi and invertebrates suggest that the gene was lost in those organisms.[8] Therefore, it is highly probable that IFFO1 originated in vertebrates.

Genus/Species Common Name Divergence from Human (MYA) Length (aa) Similarity Identity NCBI Accession
Homo sapiens Human N/A 570 100% 100% XP_006719036.1
Mus musculus Mouse 92.3 563 93% 95% XP_006506337.2
Lipotes vexillifer Baiji dolphin 94.2 573 92% 95% XP_007469487.1
Loxodonta africana African bush elephant 98.7 574 94% 96% XP_003410688.1
Chrysemys picta bellii Painted turtle 296 557 78% 84% XP_005291351.1
Pseudopodoces humilis Ground tit 296 531 76% 81% XP_005523902.1
Python bivittatus Burmese python 296 570 75% 82% XP_007429680.1
Haliaeetus leucocephalus Bald eagle 296 537 74% 79% XP_010565842.1
Rana catesbeiana American bull frog 371.2 511 25% 44% BAB63946.1
Ambystoma mexicanum Axolotl 371.2 372 24% 42% AFN68290.1
Notophthalmus viridescens Eastern newt 371.2 496 23% 45% CAA04656.1
Danio Rerio Zebra fish 400.1 640 62% 71% XP_690165.5
Poecilia formosa Amazon molly 400.1 640 57% 65% XP_007550181.1
Callorhinchus milii Australian ghostshark 462.5 512 62% 73% XP_007896103.1

Paralogs

One paralog named IFFO2 has been found in humans. The paralog is found to have 99% similarity and 99% coverage when compared to IFFO1. The paralogous sequence is highly conserved, all the way back to fish and amphibians.

Evolution

Multiple sequence alignments indicated that the Proline-Rich region from amino residues 39 to 61 near the 5' end of the sequence is highly conserved in both close and distant orthologs.[9] In addition, the filament region near the 3' end of the sequence is also highly conserved. Of the 42 conserved amino acid residues found within the IFFO1 sequence, 33 of them are found in the filament region.

When compared to fibrinogen and Cytochrome C (CYCS), IFFO1 is evolving at a moderate rate. The evolutionary history of fibrinogen demonstrates that it is a fast evolving gene, while cytochrome C has been found to be a slow evolving gene. With the most distant ortholog found to be in the Australian ghostshark, IFFO1 gene duplication took place in fish, which diverged from humans 462.5 million years ago.[10]

Protein

Structure

The predicted secondary structure of the protein consists mostly of alpha helices (47.19%) and random coils (44.74%). The building block of intermediate filaments are elongated coiled-coil dimer consisting of four consecutive alpha-helical segments.[11]

File:Predicted Tertiary Structure.png
Tertiary structure of IFFO1 protein as predicted by PHYRE2 program

Structurally, it is most similar to 1GK4, which is chain A of the human vimentin coil 2b fragment (Cys2).[12] Vimentin is a class-II intermediate filament that is found in various non-epithelial cells, especially mesenchymal cells.[13] The vimentin protein is also responsible for maintaining cell shape, integrity of the cytoplasm, and stabilizing cytoskeletal interactions.[14] Its 1A subunit, most similar to IFFO1 protein, forms a single, amphipatic alpha-helix that's compatible with a coiled-coil geometry. It is speculated that this chain is involved in specific dimer-dimer interactions during intermediate filament assembly. A "YRKLLEGEE" domain on the C-terminus is found to be important for the formation of authentic tetrameric complexes and also for the control of filament width during assembly.[15]

Expression

Based on experimental data on normal tissues in the human body, IFFO1 gene is highly expressed in the cerebellum, cerebral cortex, and especially in the spleen. Medium expression is seen in several areas such as the adrenal gland, colon, lymph nodes, thymus, and ovary. The tissue areas that had the relatively low expression includes CD4 and CD8 T-cells, epidymal cells, the heart, and the stomach. Extremely low levels of expression were observed in tissues obtained from fetus, kidney, testis, thyroid, and especially in the salivary gland. However, the gene has been found to be highly expressed in chondrosarcoma.[16] Chondrosarcoma is the cancer of the cells that generate collagen. Therefore, there seems to be an association between IFFO1's filamentous characteristic and chondrosarcoma.

Post-translational modifications

One nuclear export signal is predicted to be located at Leucine 141.[17] The IFFO1 protein is predicted to have one 11-amino acid long nuclear localization signal at 373.[18] Based on evidence, the protein is predicted to have high nuclear discrimination.[19] One negative charge acidic cluster was found from amino residue 435 to 447. One repetitive sequence PAPLSPAGP appears twice at 40 to 48 and then again from 159 to 166. This proline-rich region is found to be highly conserved. One long amino acid multiplets of 5 prolines is found at 549.

4 ubiquitination sites are found on Four different Lysine residues. They can be found at Lys78, Lys103, Lys113, Lys339.[20] Experimentally, there was evidence of 43 phosphorylation sites located on 31 serines, 7 threonines, and 5 tyrosines.[21] Furthermore, the evidence has shown with high confidence that Ser533 is a phosphorylation site specifically for protein kinase C. The phosphorylation site at Ser162 also acts as a )-glycosylated site. This type of glycosylation functions to have proteins fold properly, stabilizes the protein, and plays a role in cell-cell adhesion.[22] 4 sumolyated amino acids were found at Leu249, Leu293, Leu298, and Leu325.[23] Sumolation have several effects including interfering with the interaction between the protein’s target and its partner or provide a binding site for an interacting partner, causing conformational changes of the modified target, and facilitating or antagonizing ubiquitinization.[24] 5 glycation sites were predicted to be at Lys78, Lys256, Lys305, Lys380, and Lys478. End productions of glycation are involved in protein conformation changes, loss of function, and irreversible crosslinking.[25]

Interactions

Evidence from two-hybrid screening exists for four protein interactions with IFFO1.[26]

  • ACAP1 (ArfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 1):[27] GTPase-activating proteins for ADP ribosylation factor 6 needed for clathrin-dependent export of proteins from recycling endosome to the trans-golgi network and the cell surface [28]
  • RNF183 (Ring Finger Protein 183):[29] ring finger binding protein of zinc finger that may be involved in the ubiquitination pathways
  • GFI1B (Growth Factor-Independent 1B):[30] transcription factor that plays an important role in the development and differentiation of erythroid and megakaryocytic lineages[31]
  • XRCC4:[32] work with DNA ligase IV and DNA-dependent protein kinase in DNA repair of double-stranded breaks by non-homologous end joining

Another protein interaction with ubiquitin C was found from affinity capture-MS assay.[33]

Clinical relevance

The IFFO1 gene has not been found to be associated with any particular diseases.

References

  1. ↑ https://www.genecards.org/cgi-bin/carddisp.pl?gene=IFFO1&search=980676c18c9bbc13207ea102fa1cb9a9
  2. ↑ http://www.annualreviews.org.ezp2.lib.umn.edu/doi/abs/10.1146/annurev.bi.57.070188.003113
  3. ↑ http://www.phosphosite.org
  4. ↑ https://www.ncbi.nlm.nih.gov/protein/XP_006719036.1
  5. ↑ https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=pfam00038
  6. ↑ https://www.genecards.org/cgi-bin/carddisp.pl?gene=IFFO1&search=980676c18c9bbc13207ea102fa1cb9a9
  7. ↑ http://blast.ncbi.nlm.nih.gov/Blast.cgi
  8. ↑ https://www.genecards.org/cgi-bin/carddisp.pl?gene=IFFO1&search=980676c18c9bbc13207ea102fa1cb9a9
  9. ↑ http://seqtool.sdsc.edu/CGI/BW.cgi[permanent dead link]
  10. ↑ http://timetree.org/
  11. ↑ Strelkov SV, Herrmann H, Geisler N, Wedig T, Zimbelmann R, Aebi U, Burkhard P (March 2002). "Conserved segments 1A and 2B of the intermediate filament dimer: their atomic structures and role in filament assembly". The EMBO Journal. 21 (6): 1255–66. doi:10.1093/emboj/21.6.1255. PMC 125921. PMID 11889032.
  12. ↑ Wang Y, Addess KJ, Chen J, Geer LY, He J, He S, Lu S, Madej T, Marchler-Bauer A, Thiessen PA, Zhang N, Bryant SH (January 2007). "MMDB: annotating protein sequences with Entrez's 3D-structure database". Nucleic Acids Research. 35 (Database issue): D298–300. doi:10.1093/nar/gkl952. PMC 1751549. PMID 17135201.
  13. ↑ https://www.uniprot.org/uniprot/P08670
  14. ↑ https://www.ncbi.nlm.nih.gov/gene/7431
  15. ↑ Herrmann H, Strelkov SV, Feja B, Rogers KR, Brettel M, Lustig A, Häner M, Parry DA, Steinert PM, Burkhard P, Aebi U (May 2000). "The intermediate filament protein consensus motif of helix 2B: its atomic structure and contribution to assembly". Journal of Molecular Biology. 298 (5): 817–32. doi:10.1006/jmbi.2000.3719. PMID 10801351.
  16. ↑ https://www.ncbi.nlm.nih.gov/UniGene/ESTProfileViewer.cgi?uglist=Hs.15243
  17. ↑ http://www.cbs.dtu.dk/services/NetNES/
  18. ↑ http://nls-mapper.iab.keio.ac.jp/cgi-bin/NLS_Mapper_y.cgi
  19. ↑ http://psort.hgc.jp/
  20. ↑ https://www.genecards.org/cgi-bin/carddisp.pl?gene=IFFO1&ortholog=all&search=xp_006719036#orthologs
  21. ↑ Blom N, Gammeltoft S, Brunak S (December 1999). "Sequence and structure-based prediction of eukaryotic protein phosphorylation sites". Journal of Molecular Biology. 294 (5): 1351–62. doi:10.1006/jmbi.1999.3310. PMID 10600390.
  22. ↑ Chang C, Stewart RC (July 1998). "The two-component system. Regulation of diverse signaling pathways in prokaryotes and eukaryotes". Plant Physiology. 117 (3): 723–31. doi:10.1104/pp.117.3.723. PMC 1539182. PMID 9662515.
  23. ↑ http://sumosp.biocuckoo.org/
  24. ↑ Geiss-Friedlander R, Melchior F (December 2007). "Concepts in sumoylation: a decade on". Nature Reviews. Molecular Cell Biology. 8 (12): 947–56. doi:10.1038/nrm2293. PMID 18000527.
  25. ↑ Münch G, Schicktanz D, Behme A, Gerlach M, Riederer P, Palm D, Schinzel R (October 1999). "Amino acid specificity of glycation and protein-AGE crosslinking reactivities determined with a dipeptide SPOT library". Nature Biotechnology. 17 (10): 1006–10. doi:10.1038/13704. PMID 10504703.
  26. ↑ https://www.genecards.org/cgi-bin/carddisp.pl?gene=IFFO1&ortholog=all&search=xp_006719036#orthologs
  27. ↑ http://string-db.org/version_9_05/newstring_cgi/show_edge_details.pl?identifiers=9606.ENSP00000349364%0D9606.ENSP00000158762
  28. ↑ Jackson TR, Brown FD, Nie Z, Miura K, Foroni L, Sun J, Hsu VW, Donaldson JG, Randazzo PA (October 2000). "ACAPs are arf6 GTPase-activating proteins that function in the cell periphery". The Journal of Cell Biology. 151 (3): 627–38. doi:10.1083/jcb.151.3.627. PMC 2185579. PMID 11062263.
  29. ↑ http://string-db.org/version_9_05/newstring_cgi/show_edge_details.pl?identifiers=9606.ENSP00000349364%0D9606.ENSP00000420740
  30. ↑ http://string-db.org/version_9_05/newstring_cgi/show_edge_details.pl?identifiers=9606.ENSP00000349364%0D9606.ENSP00000344782
  31. ↑ Elmaagacli AH, Koldehoff M, Zakrzewski JL, Steckel NK, Ottinger H, Beelen DW (January 2007). "Growth factor-independent 1B gene (GFI1B) is overexpressed in erythropoietic and megakaryocytic malignancies and increases their proliferation rate". British Journal of Haematology. 136 (2): 212–9. doi:10.1111/j.1365-2141.2006.06407.x. PMID 17156408.
  32. ↑ http://string-db.org/version_9_05/newstring_cgi/show_edge_details.pl?identifiers=9606.ENSP00000349364%0D9606.ENSP00000342011
  33. ↑ http://string-db.org/version_9_05/newstring_cgi/show_edge_details.pl?identifiers=9606.ENSP00000349364%0D9606.ENSP00000344818
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