MAGEB17

MAGEB17
Identifiers
AliasesMAGEB17, MAGE family member B17
External IDsOMIM: 300763; MGI: 3645128; GeneCards: MAGEB17
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
Entrez

645864

278087

Ensembl

ENSG00000182798

ENSMUSG00000078123

UniProt

A8MXT2

n/a

RefSeq (mRNA)

NM_001277307

NM_001083629
NM_001256004

RefSeq (protein)

NP_001264236

n/a

Location (UCSC)Chr X: 16.17 – 16.17 MbChr X: 90.98 – 90.98 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Melanoma-associated antigen B17 (MAGEB17) is a protein which in humans is encoded by the MAGEB17 gene located on the X chromosome (Xp22.2). The protein has a molecular mass of approximately 37.4 kDa and an isoelectric point of approximately 9.25. MAGEB17 is classified as a cancer-testis antigen, with expression in normal adult tissues primarily restricted to germ cells and re-expression observed in a subset of human tumors.

Gene

MAGEB17 is a protein-coding gene on chromosome X (Xp22.2), on the plus strand, spanning 3,984 bp across two exons.[5] MAGEB17 is a member of the MAGEB gene family, in which the entire CDS is located within the last exon. MAGEB17 is classified as a cancer-testis antigen, with expression in normal adult tissues restricted to germ cells.[6]

The MAGEB17 gene, with MAGEB17-AS1, the antisense RNA, annotated. Source: NCBI Gene.

Transcripts

MAGEB17 produces a canonical transcript (NM_001277307.2) of 1,434 nt.[7] One splice variant exists (XM_047442355.1, 1,566 nt), differing from the canonical transcript in the 5' UTR.

Conceptual Translation of Isoform 1 of Human MAGEB17

Protein

Predicted protein structure of MAGEB17, showing alpha helices and beta sheets.

The MAGEB17 gene produces two isoforms, both 336 amino acids in length. The canonical protein, Melanoma-associated antigen B17 (NP_001264236.1), has a predicted molecular mass of ~37.4 kDa and a theoretical isoelectric point of ~9.25, indicating a basic protein at physiological pH.[8] Melanoma-associated antigen B17 isoform X1 (XP_047298311.1) is also 336 aa, differing from the canonical transcript in the 5' UTR. Gene Ontology annotations associate MAGEB17 with the negative regulation of transcription by RNA polymerase II and with activity in the nucleus.[9]

Structure

The protein contains two conserved domains: an N-terminal MAGE domain (MAGE_N, residues 5–93) and a MAGE homology domain (MHD, residues 116–283).[10] The MHD serves as a structural scaffold, a feature conserved across the MAGE protein family.[11] Multiple sequence alignments indicate that a C-terminal core region flanks the MHD and is highly conserved across mammalian orthologs.[12]

Gene level regulation

Expression

MAGEB17 is non-ubiquitously expressed, with expression in normal adult tissues restricted to germ cells.[13] Testis is the predominant site of expression, with all other normal adult tissues at near-zero levels.[14] Expression is transiently detected in fetal heart tissue at 18 weeks gestational age.[15] No substantial expression has been detected in any brain region in either fetal or adult tissue.[16] In cancer, MAGEB17 is reactivated across a subset of tumor types including colon, rectal, and liver adenocarcinomas, and testicular germ cell tumors.[17]

Promoter

The MAGEB17 promoter contains binding sites for transcription factors associated with cancer-testis antigen reactivation and germ cell biology, including STAT3, SRY, Nanog, and CREM.[18] Promoter sequence conservation is largely restricted to primates, consistent with the primate-specific distribution of the MAGE gene family.[19]

Protein level regulation

MAGEB17 contains several experimentally confirmed and predicted regulatory modifications. Threonine 131 (T131), located at the MHD boundary, has been experimentally identified as a phosphorylation site and is conserved across mammalian orthologs.[20] Two predicted SUMOylation sites exist at K88 and K292.[21] A predicted SPOP degron motif is present at residues 39–43. A predicted MAPK docking motif at residues 152–160 suggests potential regulation by mitogen-activated protein kinase signaling.

Subcellular localization

MAGEB17 localizes primarily to the nucleus, consistent with two predicted nuclear localization signals at residues 7–12 and 126–145.[22] A cytoplasmic pool has also been observed, potentially reflecting pre-import localization prior to nuclear transport.

Homology and evolution

Paralogs

Comparison of MAGEB17, MAGEB4, and MAGEB1 paralogs across species with properties.

MAGEB17 is a member of the MAGE protein family, which comprises over 50 paralogs in humans.[23] MAGEB4 shares greater sequence identity with MAGEB17 than MAGEB1, suggesting a closer evolutionary relationship within the MAGE-B subfamily.[24]

Orthologs

Table of MAGEB1's Orthologs and related properties.

MAGEB17 orthologs are found exclusively in mammals, consistent with the mammal-specific expansion of the MAGE protein family.[25] Sequence identity decreases with increasing evolutionary distance from humans.[26]

Phylogenetic Tree of MAGEB17

Rate of divergence

Figure 5: Corrected Sequence Divergence vs. Median Date of Divergence. Graph made on Microsoft Excel, using data from NIH.

MAGEB17 diverges more rapidly than both Cytochrome c and Complement factor I, suggesting relatively weak purifying selection on the protein sequence compared to these broadly expressed proteins.[27]

Distant homologs

The most distant detectable homolog is the Drosophila melanogaster MAGE protein, sharing 16.9% sequence identity with human MAGEB17, with conservation restricted to the MAGE homology domain.[28]

Interacting proteins

MAGEB17 Protein Interactions - Source:STRING

STRING analysis identifies several predicted functional partners for MAGEB17, primarily on the basis of co-expression and text mining.[29] No experimentally validated protein-protein interactions have been identified for MAGEB17 in BioGRID. A single genetic interaction with LDLR is recorded, though this is considered a likely artifact given the high-throughput nature of the screen.[30]

Clinical significance

MAGEB17 is classified as a cancer-testis antigen, with expression silenced in normal somatic tissues via DNA methylation and reactivated in a subset of tumors.[31] RNA expression data indicate enrichment in colon, rectal, and liver adenocarcinomas, and testicular germ cell tumors.[32] A stop-gain variant (V297*) has been identified, resulting in a truncated protein.[33] By virtue of its tumor-specific expression, MAGEB17 represents a potential target for cancer immunotherapy.[34]

Because of its tumor-associated expression pattern, MAGEB17 has been proposed as a potential target for cancer immunotherapy.

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000182798 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000078123 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ NCBI Gene entry 645864. https://www.ncbi.nlm.nih.gov/gene/645864
  6. ^ Chomez P, et al. An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res. 2001;61(14):5544–5551. PMID: 11454705.
  7. ^ NCBI Gene entry 645864. https://www.ncbi.nlm.nih.gov/gene/645864
  8. ^ UniProt Consortium. UniProtKB entry A8MXT2 (MAGEB17_HUMAN). https://www.uniprot.org/uniprotkb/A8MXT2/entry
  9. ^ QuickGO — GO annotations for UniProtKB:A8MXT2. European Bioinformatics Institute. https://www.ebi.ac.uk/QuickGO/annotations?geneProductId=A8MXT2
  10. ^ NCBI Gene entry 645864. https://www.ncbi.nlm.nih.gov/gene/645864
  11. ^ Chomez P, et al. An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res. 2001;61(14):5544–5551. PMID: 11454705.
  12. ^ Clustal Omega multiple sequence alignment of 20 MAGEB17 orthologs. https://www.ebi.ac.uk/jdispatcher/msa/clustalo
  13. ^ Human Protein Atlas — MAGEB17 single-cell RNA expression. https://www.proteinatlas.org/ENSG00000182798-MAGEB17
  14. ^ Human Protein Atlas — MAGEB17 tissue RNA expression (PRJEB4337). https://www.proteinatlas.org/ENSG00000182798-MAGEB17
  15. ^ Szabo L, et al. Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development. Genome Biol. 2015;16(1):126. PMID: 26076956.
  16. ^ BrainSpan Atlas of the Developing Human Brain — MAGEB17. https://www.brainspan.org
  17. ^ Human Protein Atlas — MAGEB17 cancer RNA expression (TCGA). https://www.proteinatlas.org/ENSG00000182798-MAGEB17
  18. ^ UCSC Genome Browser — Zoonomia 241-way placental mammal conservation, GRCh38 chrX:16,167,481–16,171,464. https://genome.ucsc.edu
  19. ^ UCSC Genome Browser — Zoonomia 241-way placental mammal conservation, GRCh38 chrX:16,167,481–16,171,464. https://genome.ucsc.edu
  20. ^ PhosphoSitePlus entry for MAGEB17. https://www.phosphosite.org/proteinAction.action?id=19104250
  21. ^ GPS-SUMO 2.0 analysis of NP_001264236.1.
  22. ^ Human Protein Atlas — MAGEB17 subcellular localization. https://www.proteinatlas.org/ENSG00000182798-MAGEB17
  23. ^ Chomez P, et al. An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res. 2001;61(14):5544–5551. PMID: 11454705.
  24. ^ Clustal Omega multiple sequence alignment of MAGEB17, MAGEB1, and MAGEB4. https://www.ebi.ac.uk/jdispatcher/msa/clustalo
  25. ^ Chomez P, et al. An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res. 2001;61(14):5544–5551. PMID: 11454705.
  26. ^ NCBI BLAST; EMBOSS Needle pairwise alignment. https://www.ebi.ac.uk/jdispatcher/psa/emboss_needle
  27. ^ TimeTree — The Timescale of Life. https://timetree.org
  28. ^ EMBOSS Needle pairwise alignment. https://www.ebi.ac.uk/jdispatcher/psa/emboss_needle
  29. ^ STRING v12 — MAGEB17 functional protein association network. https://string-db.org
  30. ^ BioGRID v5 — MAGEB17 interactions. https://thebiogrid.org
  31. ^ Chomez P, et al. An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res. 2001;61(14):5544–5551. PMID: 11454705.
  32. ^ Human Protein Atlas — MAGEB17 cancer RNA expression (TCGA). https://www.proteinatlas.org/ENSG00000182798-MAGEB17
  33. ^ UniProt Consortium. UniProtKB entry A8MXT2 (MAGEB17_HUMAN). https://www.uniprot.org/uniprotkb/A8MXT2/entry
  34. ^ Chomez P, et al. An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res. 2001;61(14):5544–5551. PMID: 11454705.

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