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Protein FAM89A (family with sequence similarity 89, member A) is a protein which in humans is encoded by the FAM89A gene. It is also known as chromosome 1 open reading frame 153 (C1orf153). Highest FAM89A gene expression is observed in the placenta and adipose tissue. Though its function is largely unknown, FAM89A is found to be differentially expressed in response to interleukin exposure, and it is implicated in immune responses pathways and various pathologies.



Gene

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FAM89A located downstream of the ARV1 gene.

The gene FAM89A is a protein-encoding gene in humans, located on minus strand of chromosome 1, map position 1q42.2. It is also known as chromosome 1 open reading frame 153 (C1orf153)[1][2][3]. The primary mRNA transcript for the FAM89A gene is 1,503 base pairs in length[4]. There are no other transcript variants for FAM89A. The gene is composed of two exons flanking one large intronic region[5]. FAM89A is neighboring the genes TRIM67 (Tripartite Motif Containing 67), located downstream of FAM89A on the plus strand of chromosome 1, and ARV1 (ARV1 Homolog, Fatty Acid Homeostasis Modulator), located upstream of FAM89A on the plus strand of chromosome 1[5][6].

Protein

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Biochemistry

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The FAM89A protein is 184 amino acids in length, and it has a predicted molecular mass of 18.6kDa and a predicted isoelectric point of 5.64[7]. FAM89A shows five periodic repeats of leucine residues at every seventh amino acid position at positions 81-115, which is characteristic of its predicted leucine zipper structural motif[8][9].

Conserved Domains

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FAM89A contains a conserved leucine-rich adapter protein domain (LURAP), located at amino acid positions 84-122[10][11]. The LURAP superfamily of proteins are activators of the canonical NF-κB pathway, involved in promoting antigen presentation in dendritic cells and the production of pro-inflammatory cytokines[12].

Secondary Structure

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FAM89A is predicted to be 40% alpha helix, 11% extended strand, and 49% random coils[13]. The conserved LURAP domain is predicted to form an alpha helix[14][15][16][17].

 
Promoter sequence of FAM89A with annotated predicted transcription factor binding sites.

Tertiary Structure

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FAM89A tertiary structure has not yet been determined by X-ray crystallography. I-TASSER software predicts dimerization of alpha helix monomers, indicative of the leucine zipper motif[15][16][17].

Gene Level Regulation

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Promoter

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The FAM89A promoter region is 1,104 base pairs in length[18]. It contains binding sites for various transcription factors, including TFIIB (RNA polymerase II transcription factor IIB), PLAG1 (pleomorphic adenoma gene 1), MZF1 (myeloid zinc finger 1 factors), and SP1 (GC-Box factors SP1/GC)[5][18].

Expression pattern

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Immunofluorescent staining of RH-30 cell line reveals FAM89A localization to Golgi appartus, vesicles, and nucleoplasm (shown in green)[19].

FAM89A's highest expression is observed in the placenta and adipose tissue[20][21]. RNA-sequencing data also reveals moderate FAM89A expression in the adrenal gland, lung, skin, spleen, and breast[2][6]. Microarray hybridization supports high FAM89A expression in the placenta and moderate expression in the lung, spinal cord, skin, adrenal gland, and retina[22].

Protein Level Regulation

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Subcellular Localization

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The FAM89A protein is suggested to be localized in the nucleoplasm, Golgi apparatus, and/or vesicles[23][24][25].

Post-translational Modifications

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Phosphorylation/O-Linked β-N-acetylglucosamine

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FAM89A has three predicted phosphorylation sites located at amino acid positions 30, 32, and 168 that are conserved in distant orthologs[26]. The predicted phosphorylation site at position 32 is experimentally verified at position 28 in its paralog, FAM89B[27].

There is a potential competitive binding site for phosphorylation and O-linked β-N-acetylglucosamine (O-GlcNAc) at position 158[28], supporting localization of FAM89A in the nucleoplasm[23][24].

Glycation

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NetGlycate 1.0 server predicts two glycation sites at positions 57 and 95[29]. The residues are conserved in distant FAM89A orthologs.

 
Schematic diagram of FAM89A 184 amino acid (aa) length protein with annotations of post-translational modifications.

SUMOylation

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SUMOplot analysis program predicts SUMO (Small Ubiquitin-like Modifier) protein sites at position 83. The residue is conserved in distant FAM89A orthologs.

Homology/Evolution

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Pairwise sequence alignment of FAM89A to its paralog, FAM89A, reveals an unidentified conserved region containing experimentally verified FAM89B phosphorylation site.

Paralogs

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An important human paralog of FAM89A is FAM89B, located on human chromosome 11 at map position 11q13.1[30]. FAM89B is also known as, Leucine Repeat Adaptor Protein 25 (LRAP25) and Mammary Tumor Virus Receptor Homolog 1 (MTVR1)[30]. Orthologs of FAM89A, but not FAM89B, are present in bivalves, crinoids, hemichordates, starfish, and horseshoe crabs[31]. Orthologs of FAM89B, but not FAM89A, are present in brachiopods and priapulids, The paralogs likely split around 736 million years ago[32].

Orthologs

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FAM89A is largely conserved in Eutelostomi (bony vertebrates). Its orthologs can be found in mammals, amphibians, reptiles, birds, fish, and various insects[33]. Distant FAM89A orthologs are present in octopus, scallop, ants, and bees[34][35][36][37].

Fam89A Orthologs
Genus and Species Common Name Taxonomic Group (Order) Median Date of Divergence from Human Lineage (MYA) Accession # Sequence Identity (%)
Homo sapiens Human Primates - NP_940954 -
Rattus Norvegicus Brown Rat Rodentia 89 NP_001011711 79.3%
Acinonyx Jubatus Cheetah Carnivora 94 XP_026902687 92.9%
Felis Catus Cat Carnivora 94 XP_023096185 92.4%
Canis lupus dingo Dingo Carnivora 94 XP_025304333 91.3%
Neomonachus schauinslandi Hawaiian Monk Seal Carnivora 94 XP_021551830 90.8%
Physeter catodon Sperm Whale Even-toed ungulates 94 XP_023972851 90.2%
Bubalus bubalis Water Buffalo Even-toed ungulates 94 XP_006055609 88.6%
Rousettus aegyptiacus Egyptian Fruit Bat Chiroptera 94 XP_016018927 75.5%
Nothoprocta perdicaria Chilean Tinamou Tinamiformes 318 XP_025909144 61.1%
Gekko japonicus Schlegel's Japanese gecko Squamata 318 XP_015284726.1 49.8%
Xenopus laevis African Clawed Frog Anura 351.7 NP_001121297 65.6%
Microcaecilia unicolor Tiny Cayenne Caecilian Gymnophiona 351.7 XP_030051069 63.6%
Scleropages formosus Asian Arowana Osteoglossiformes 433 XP_018597917 52.6%
Callorhincus milii Australian Ghost Shark Chimaeriformes 465 XP_007893339 54.5%
Acanthaster planci Crown-of-thorns Starfish Valvatida 627 XP_022103224 30.8%
Branchiostoma belcheri Lancelet Amphioxiformes 637 XP_019630993.1 27.1%
Parasteatoda tepidariorum Common House Spider Araneae 736 XP_015922370 32.8%
Mizuhopecten Yessoensis Scallop Pectinida 736 XP_021378459 22.0%
Octopus Vulgaris Common Octopus Octopoda 736 XP_029642735 19.2%
Cyphomyrmex costatus Fungus-growing ant Hymenoptera 736 KYN04870.1 10.9%
Eufriesea Mexicana Orchid Bee Hymenoptera 736 OAD57070 10.5%
 
Relative divergence of FAM89A reveals FAM89A's rapid rate of mutation accumulation relative to fibrinogen, a gene that is evolving rapidly, and cytochrome c, a gene that is evolving slowly.

Evolution

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The rate of accumulation of amino acid changes relative to the genes Fibrinogen and Cytochrome c indicates that FAM89A is evolving rapidly, using the molecular clock technique.

Interacting Proteins

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FAM89A is experimentally determined to interact with the UBXN2B (UBX Domain Protein 2B), an adaptor protein involved in biogenesis in the Golgi apparatus and endoplasmic reticulum (ER) and assembly and maintenance of the ER during the cell cycle[38][39]

Clinical Significance

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Pathology and Disease Association

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FAM89A is suggested to be involved in modulating the effects of smoking on the risk of atherosclerotic plaque burden[40]. In a study conducted in 2014, a cohort of 264 Caribbean Hispanics with varying smoking frequencies were evaluated for carotid plaque burden and 11 single nucleotide polymorphism (SNP) were identified that had a notable interaction with smoking effects on carotid plaque burden, including SNP rs6700792, located within the FAM89A gene[40].

FAM89A is also suggested to be involved in discriminating viral and bacterial infection in febrile patients[41]. A 2016 study conducted at the Division of Infectious Disease in the Imperial College of London evaluated blood-based transcriptomic biomarkers and revealed that febrile patients with bacterial infection displayed increased expression of FAM89A[42][43].

Microarray hybridization data revealed slight decrease in FAM89A expression in response to airway epithelial cell exposure to interleukin 13 and CD8+ T lymphocyte exposure to interleukin 10[44][45].

References

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  1. ^ "Transcript: FAM89A-001 (ENST00000366654.4) - Summary - Homo sapiens - GRCh37 Archive browser 100". grch37.ensembl.org. Retrieved 2020-05-02.
  2. ^ a b "FAM89A protein expression summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2020-05-02.
  3. ^ "Parental Gene". www.bioinfo.mochsl.org.br. Retrieved 2020-05-02.
  4. ^ "AceView: Gene:FAM89A, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView". www.ncbi.nlm.nih.gov. Retrieved 2020-05-02.
  5. ^ a b c "Human hg38 chr1:231,018,958-231,040,254 UCSC Genome Browser v397". genome.ucsc.edu. Retrieved 2020-05-03.
  6. ^ a b "FAM89A family with sequence similarity 89 member A [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  7. ^ "ExPASy - Compute pI/Mw tool". web.expasy.org. Retrieved 2020-05-02.
  8. ^ "PSORT II Prediction". psort.hgc.jp. Retrieved 2020-05-03.
  9. ^ "SAPS < Sequence Statistics < EMBL-EBI". www.ebi.ac.uk. Retrieved 2020-05-03.
  10. ^ "CDD Conserved Protein Domain Family: LURAP". www.ncbi.nlm.nih.gov. Retrieved 2020-05-02.
  11. ^ "RecName: Full=Protein FAM89A - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-05-02.
  12. ^ "CDD Conserved Protein Domain Family: LURAP". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  13. ^ "NPS@ : GOR4 secondary structure prediction". npsa-prabi.ibcp.fr. Retrieved 2020-05-03.
  14. ^ "CFSSP: Chou & Fasman Secondary Structure Prediction Server". www.biogem.org. Retrieved 2020-05-03.
  15. ^ a b Zhang, Yang (2009). "I-TASSER: Fully automated protein structure prediction in CASP8". Proteins: Structure, Function, and Bioinformatics. 77 (S9): 100–113. doi:10.1002/prot.22588. ISSN 0887-3585.
  16. ^ a b Roy, Ambrish; Yang, Jianyi; Zhang, Yang (2012-05-08). "COFACTOR: an accurate comparative algorithm for structure-based protein function annotation". Nucleic Acids Research. 40 (W1): W471–W477. doi:10.1093/nar/gks372. ISSN 0305-1048.
  17. ^ a b Yang, Jianyi; Zhang, Yang (2015-04-16). "I-TASSER server: new development for protein structure and function predictions". Nucleic Acids Research. 43 (W1): W174–W181. doi:10.1093/nar/gkv342. ISSN 0305-1048.
  18. ^ a b "ElDorado: Annotation & Analysis". www.genomatix.de. Retrieved 2020-05-03.
  19. ^ "Cell atlas - FAM89A - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2020-05-03.
  20. ^ "FAM89A - Protein FAM89A - Homo sapiens (Human) - FAM89A gene & protein". www.uniprot.org. Retrieved 2020-05-02.
  21. ^ "Gene: FAM89A - ENSG00000182118". bgee.org. Retrieved 2020-05-02.
  22. ^ "GDS3113 / 211045". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  23. ^ a b "FAM89A Gene - GeneCards | FA89A Protein | FA89A Antibody". www.genecards.org. Retrieved 2020-05-03.
  24. ^ a b "FAM89A - Antibodies - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2020-05-03.
  25. ^ "PSORT Users' Manual". psort.hgc.jp. Retrieved 2020-05-03.
  26. ^ "NetPhos 3.1 Server". www.cbs.dtu.dk. Retrieved 2020-05-03.
  27. ^ "RecName: Full=Leucine repeat adapter protein 25 - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  28. ^ "YinOYang 1.2 Server". www.cbs.dtu.dk. Retrieved 2020-05-03.
  29. ^ "NetGlycate 1.0 Server". www.cbs.dtu.dk. Retrieved 2020-05-03.
  30. ^ a b "FAM89B Gene - GeneCards | LRA25 Protein | LRA25 Antibody". www.genecards.org. Retrieved 2020-05-02.
  31. ^ "BLAST: Basic Local Alignment Search Tool". blast.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  32. ^ "TimeTree :: The Timescale of Life". www.timetree.org. Retrieved 2020-05-03.
  33. ^ "ortholog_gene_375061[group] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  34. ^ "protein FAM89A-like [Mizuhopecten yessoensis] - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  35. ^ "protein FAM89A-like [Octopus vulgaris] - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  36. ^ "Protein FAM89A [Cyphomyrmex costatus] - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  37. ^ "Protein FAM89A [Eufriesea mexicana] - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  38. ^ "FAM89A protein (human) - STRING interaction network". string-db.org. Retrieved 2020-05-03.
  39. ^ "UBXN2B Gene - GeneCards | UBX2B Protein | UBX2B Antibody". www.genecards.org. Retrieved 2020-05-03.
  40. ^ a b Della-Morte, David; Wang, Liyong; Beecham, Ashley; Blanton, Susan H.; Zhao, Hongyu; Sacco, Ralph L.; Rundek, Tatjana; Dong, Chuanhui (2014-09-15). "Novel Genetic Variants Modify the Effect of Smoking on Carotid Plaque Burden in Hispanics". Journal of the neurological sciences. 344 (0): 27–31. doi:10.1016/j.jns.2014.06.006. ISSN 0022-510X. PMC 4143440. PMID 24954085.
  41. ^ Gómez-Carballa, Alberto; Cebey-López, Miriam; Pardo-Seco, Jacobo; Barral-Arca, Ruth; Rivero-Calle, Irene; Pischedda, Sara; Currás-Tuala, María José; Gómez-Rial, José; Barros, Francisco; Martinón-Torres, Federico; Salas, Antonio (2019-08-13). "A qPCR expression assay of IFI44L gene differentiates viral from bacterial infections in febrile children". Scientific Reports. 9 (1): 1–12. doi:10.1038/s41598-019-48162-9. ISSN 2045-2322.
  42. ^ Herberg, Jethro A.; Kaforou, Myrsini; Wright, Victoria J.; Shailes, Hannah; Eleftherohorinou, Hariklia; Hoggart, Clive J.; Cebey-López, Miriam; Carter, Michael J.; Janes, Victoria A.; Gormley, Stuart; Shimizu, Chisato (2016-08-23). "Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children". JAMA. 316 (8): 835–845. doi:10.1001/jama.2016.11236. ISSN 0098-7484.
  43. ^ Kaforou, Myrsini; Herberg, Jethro A.; Wright, Victoria J.; Coin, Lachlan J. M.; Levin, Michael (2017-04-18). "Diagnosis of Bacterial Infection Using a 2-Transcript Host RNA Signature in Febrile Infants 60 Days or Younger". JAMA. 317 (15): 1577–1578. doi:10.1001/jama.2017.1365. ISSN 0098-7484.
  44. ^ "GDS4981 / ILMN_2285817". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
  45. ^ "GDS4217 / 10582694". www.ncbi.nlm.nih.gov. Retrieved 2020-05-03.
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