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FAM203B

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Family with Sequence Similarity 203, Member B (FAM203B) is a protein encoded by the FAM203B gene (8q24.3) in humans[1][2]. While FAM203B is only found in humans and possibly non-human primates, its paralog, FAM203A[3], is highly conserved[4]. The FAM203B protein contains two conserved domains of unknown function, DUF383 and DUF384[4], and no transmembrane domains[5]. This protein has no known function as of yet, although the homolog of FAM203A in Caenorhabditis elegans (Y54H5A.2) is thought to help regulate the actin cytoskeleton[6].

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Gene

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FAM203B is located on the positive DNA strand of the long arm of chromosome 8 at locus 24.3 (8q24.3) from 76,368,898 - 76,371,411 in the human genome. The gene product contains 2,402 bp of mRNA with 6 predicted exons in the human gene[2][7]. There are no known isoforms.

File:Chromosome 8 (locus 8q24.3).png
Diagram of chromosome 8 with locus 8q24.3 highlighted in red[8].


 
FAM203B mRNA tissue expression levels[8].

Gene Neighborhood

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The pseudogene TSSK5P2 is located on the negative strand opposite FAM203B (145,440,975 - 145,443,775)[9], while LOC377711 is located immediately downstream on the positive strand (145,448,755 - 145,485,896)[10]. FAM203A, MROH1, and SCXB are located upstream of FAM203B[7][11].

Gene Expression

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Expression Profile: mRNA expression has been localized in many tissue types (immune, nervous, muscle, internal, secretory, and reproductive) in similar quantities and may therefore be ubiquitous[8].

Promoter: The predicted promoter region of FAM203B is located between 145,437,380 and 145,438,015 on Chromosome 8 and has a length of 636 bp[12].


File:Tertiary structure 2.PNG
Tertiary structure prediction for FAM203B generated by the Phyre 2.0 server[13].

Protein

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The function of FAM203B is not currently understood. The FAM203B protein has 390 amino acids[1], a molecular weight of 42.1 kdal[5], and an isoelectric point of 4.56[14].

Structure

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FAM203B contains two domains of unknown function: DUF383 (residues 110-288) and DUF384 (residues 292-349)[1]. The protein is alanine-, proline-, and leucine-rich, but poor in serine, asparagine, threonine, isoleucine, lysine, and phenylalanine. The following internal repeats can be found in the primary sequence: LPFL (26-29, 245-248), ELAP (70-73), GRAL (54-57, 111-114), and LAADPGL (88-94, 99-105). There are no positive, negative, mixed charge, or hydrophobic clusters; no transmembrane domains; and no clusters of amino acid multiplets[5]. The secondary structure prediction generated by the Phyre 2.0 bioinformatic server shows only α-helices, almost all of which have high confidence values. The overall confidence value of the model is 99.5%[13].

Post-Translational Modifications

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There are at least six predicted phosphorylation sites in FAM203B: S17, S153, Y167, T223, S259, and S320[15]. The FAM203B protein is also predicted to locate to the cytoplasm[16].

Protein Interactions

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There are many possible transcription factor binding sites in the FAM203B promoter. Below is a table of the best possibilities, which have high confidence values, evolutionary conservation, and/or multiple possible binding sites in the promoter[12].


Table of Possible Transcription Factor Binding Sites in Predicted FAM203B Promoter[12]:

Transcription Factor Start End Strand Sequence
Winged-helix transcription factor IL-2 enhancer binding factor, forkhead box K2 6 22 - gacaggacAACAcaggg
Hypermethylated in Cancer 1 49 61 + ccgTGCCagcctg
Zinc finger transcription factor ZBP-89 94 116 + tggccactCCCCcattcagccct
Kidney-enriched kruppel-like factor, KLF15 142 158 + gagccGGGGcgcgggcc
Transcription factor II B recognition element 149 155 - ccgCGCC
Glial cells missing homolog 1, chorion-specific transcription factor GCMα 159 173 + tcagaCCCTcagggc
Transcription factor AP-2α 161 175 - gggcCCTGagggtct
Smad4 transcription factor involved in TGFβ signaling 245 255 - gtaGTCTcggc
Nuclear factor 1 278 298 - gatTTGGccgcctgccgcgtc
ZF5 POZ domain zinc finger, zinc finger protein 161 295 309 + aatCGCGccgggcct
Smad3 transcription factor involved in TGFβ signaling 365 375 - ggcGTCTggcc
Myeloid zinc finger protein MZF1 384 394 - gcGGGGagtta
X-linked zinc finger protein 397 407 + gcGGCCtggcc
Myeloid zinc finger protein MZF1 406 416 - gaGGGGagggg
Core promoter-binding protein with 5 kruppel-type zinc fingers 423 445 + ccggtcCCGCcccttgagcccag
X gene core promoter element 1 424 434 - ggGCGGgaccg
Zinc finger and BTB domain-containing 7A 479 501 - cgcaaCCCCgcccaccagaggag
Kruppel-like factor 7 483 499 + tctggtgGGCGgggttg
Erythroid kruppel-like factor 533 549 + ggcaccggtcGGGTggc
Hypermethylated in cancer 1 541 553 - tgcTGCCacccga


There are several other proteins that may interact directly with the FAM203B protein including C1orf112, HEATR3, MRTO4, BYSL, GINS1, DKC1, TXNDC12, PWP2, IMP4, and NIP7[17].


Homology and Evolution

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FAM203A: Paralog

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FAM203A is 99% identical to FAM203B with only one amino acid difference (E264Q) due to a point mutation (G857C)[18][1][11]. This indicates that the duplication event that produced FAM203B 242,266 bp downstream[7] from FAM203A occurred very recently in evolutionary history. The FAM203A protein is highly conserved and has orthologs in primates, rodents, ungulates, marsupials, amphibians, fish, fungi, plants, and at least one monotreme, one reptile, and one hemichordate[4][19].

Orthologs and Homologs

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Table of FAM203B Paralog and Homologs:

Scientific Name Common Name Divergence from Humans (MYA)[20] NCBI Protein Accession Gene Name Protein Length Sequence Similarity
Homo sapiens Human 0.0 NP_057542 FAM203A 390 100%
Macaca mulatta Rhesus macaque 29.2 XM_001090013 BRP16L 396 94%
Pan troglodytes Chimpanzee 6.3 XP_520011 FAM203A 395 98%
Mus musculus Mouse 92.3 NP_067530 FAM203A 393 86%
Sus scrofa Wild boar 94.2 XP_003125495 FAM203A-like 406 85%
Monodelphis domestica Gray short-tailed opossum 162.6 XP_003340757 FAM203A-like 483 78%
Columba livia Rock dove 296.0 EMC87403 BRP16 (partial) 194 64%
Danio rerio Zebrafish 400.1 NP_001002522 FAM203A 377 70%
Xenopus tropicalis Western clawed frog 371.2 AAI60980 LOC100145412 377 70%
Xenopus tropicalis Western clawed frog 371.2 NP_001007916 FAM203A 359 68%
Strongylocentrotus purpuratus Purple sea urchin 742.9 XP_793139 FAM203A-like 372 62%
Anolis carolinensis Carolina anole 301.7 XP_003228921 BRP16L 286 57%
Saccoglossus kowglevski Acorn worm 661.2 XP_002739897 BRP16L 362 61%
Danio rerio Zebrafish 400.1 XP_002665502 BRP16L 181 57%
Saccharomyces cerevisiae Budding yeast 1369.0 NP_011703 Hgh1p 394 52%
Arabidopsis thaliana Thale cress 1369.0 NP_172882 Armadillo/beta-catenin-like repeats-containing 339 49%

There is one ortholog of FAM203B, brain protein 16-like (BRP16L) in Macaca mulatta[4][19], although no other primates appear to have orthologous proteins. There are two possible explanations for this anomaly: (1) DNA of other primates has not been sequenced thoroughly in the genomic region of the FAM203B ortholog, or (2) FAM203B is the result of a gene duplication event unique to humans, meaning that BRP16L in M. mulatta resulted from an earlier duplication event unique to that species. The second explanation is supported by the following evidence:

  1. Like M. mulatta, Danio rerio has both a FAM203A gene and a BRP16L gene. The large amount of time since the divergence of the M. mulatta and D. rerio lineages suggests that these BRP16L genes are the result of separate duplication events.
  2. The BRP16L protein in D. rerio has a significant 3’ truncation compared to the M. mulatta protein, further supporting the hypothesis that these proteins evolved separately[21][22][18].
  3. If the BRP16L genes in "M mulatta" and "D. rerio" are the result of separate duplication events, then it is also possible that FAM203B and BRP16L in "M. mulatta" are the result of separate duplication events.
  4. BRP16 (brain protein 16) is an alias of FAM203A, and BRP16L (brain protein 16-like) is an alias of FAM203B. A gene named BRP16L simply means that the gene is related to FAM203A but not necessarily to FAM203B.
  5. FAM203A and FAM203B are located in the telomeric region of chromosome 8, an area of chromosomes that frequently experiences recombination events.

However, because FAM203A and FAM203B are so similar, it is difficult to determine whether proteins are orthologs or just simply homologs.

Phylogeny

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The phylogenetic tree of FAM203B and its homologs matches with the overall divergence of the respective lineages[18][20].

Conserved Domains, Motifs, and Residues

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  1. ARM (armadillo/beta-catenin-like repeats-containing): Found in two homologs (FAM203A in Danio rerio and At1g14300 in Arabidopsis thaliana) and overlaps slightly with the beginning of the DUF383 domain. Related to the HEAT domain, consists of a 40-amino-acid tandemly repeated sequence motif, and is thought to mediate protein-protein interactions. Several eukaryotic genes contain ARM domains including armadillo in Drosophila melanogaster, beta-catenin, plakoglobin, and adenomatous polyposis coli in mammals[4].
  2. DUF383: Domain of unknown function 383
  3. DUF384: Domain of unknown function 383

Every ortholog and homolog of FAM203B has a DUF383 domain and a DUF384 domain (except Anolis carolinensis, which is missing DUF384 due to a large 3' truncation[23][19]). There is significant variation among mammals, marsupials, and monotremes as to where the DUF383 domain begins, whereas this variation is smaller in reptiles, amphibians, fish, invertebrates, plants, and fungi. Additionally, the DUF383 domain ends at the same location for all homologs, while the DUF384 domain starts and ends at roughly the same location in all homologs. There is high homology in the DUF384 domain (292..349) and in the DUF383 domain (154..288), and several amino acids are completely conserved in vertebrates, invertebrates, plants, and fungi, which include Arg190, Gly219, Asn226, Lys273, and Lys338. Other highly conserved amino acids include Asn87, Lys88, Arg216, and Phe229[4][18].


References

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  1. ^ a b c d "Predicted: protein FAM203B [Homo sapiens]". NCBI Protein. Retrieved 5 February 2013.
  2. ^ a b "Predicted: Homo sapiens family with sequence similarity 203, member B (FAM203B, mRNA". NCBI Nucleotide. Retrieved 5 February 2013.
  3. ^ "FAM203 family". NextProt Beta. Retrieved 5 February 2013.
  4. ^ a b c d e f "HomoloGene: 48742, gene conserved in Eukaryota". NCBI HomoloGene. Retrieved 18 January 2013.
  5. ^ a b c Brendel, Volker. "SAPS (Statistical Analysis of PS)".
  6. ^ Fievet, Bruno Thomas; Rodriguez, Josana; Naganathan, Sundar; Lee, Christine; Zeiser, Eva; Ishidate, Takao; Shirayama, Masaki; Grill, Stephan; Ahringer, Julie (2013). "Systemic genetic interaction screens uncover cell polarity regulators and functional redundancy". Nature Cell Biology. 15 (1): 103–112. doi:10.1038/ncb2639. PMC 3836181. PMID 23242217. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  7. ^ a b c "FAM203B family with sequence similarity 203, member B [Homo sapiens (human)]". NCBI Gene. Retrieved 5 February 2013.
  8. ^ a b c "FAM203B Gene". Weizmann Institute of Science. Retrieved 9 May 2013.
  9. ^ "TSSK5P2 testis-specific serine kinase 5 pseudogene 2 [Homo sapiens (human)]". NCBI Gene. Retrieved 10 May 2013.
  10. ^ "LOC377711 HEAT repeat-containing protein 7A-like [Homo sapiens (human)]". NCBI Gene. Retrieved 10 May 2013.
  11. ^ a b "FAM203A family with sequence similarity 203, member A [Homo sapiens (human)]". NCBI Gene. Retrieved 10 May 2013.
  12. ^ a b c "Genomatix El Dorado". Retrieved 7 April 2013.
  13. ^ a b Kelley, Lawrence A.; Sternberg, Michael J E. (2009). "Protein structure prediction on the web: a case study using the Phyre server". Nature Protocols. 4 (3): 363–371. doi:10.1038/nprot.2009.2. hdl:10044/1/18157. S2CID 12497300.{{cite journal}}: CS1 maint: date and year (link)
  14. ^ Toldo, Luca. "PI (Isoelectric Point Determination)".
  15. ^ Blom, N (1999). "Sequence- and structure-based prediction of eukaryotic protein phorphorylation sites". Journal of Moleculary Biology. 294 (5): 1351–1362. doi:10.1006/jmbi.1999.3310. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  16. ^ Horton, Paul. "PSORT II".
  17. ^ "C8orf30B Predicted Functional Partners". STRING: functional protein association networks. Retrieved 9 May 2013.
  18. ^ a b c d Cite error: The named reference CLUSTALW was invoked but never defined (see the help page).
  19. ^ a b c "BLAST: Basic Local Alignment Search Tool". NCBI BLAST. Retrieved 5 February 2013.
  20. ^ a b Hedges, S. Blair; Dudley, Joel; Kumar, Sudhir (2006). "TimeTree: a public knowledge-base of divergence times among organisms". Bioinformatics. 22 (23): 2971–2972. doi:10.1093/bioinformatics/btl505. PMID 17021158.{{cite journal}}: CS1 maint: date and year (link)
  21. ^ "Predicted: brain protein 16-like [Macaca mulatta]". NCBI Protein. Retrieved 5 February 2013.
  22. ^ "Predicted: brain protein 16-like [Danio rerio]". NCBI Protein. Retrieved 5 February 2013.
  23. ^ "Predicted: brain protein 16-like [Anolis carolinensis]". NCBI Protein. Retrieved 10 May 2013.
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