FAM63A

Family with sequence similarity 63, member A is a protein that, in humans, is encoded by the FAM63A gene. It is located on the minus strand of chromosome 1 at locus 1q21.3.[5]

MINDY1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 5JKN, 5JQS
Identifiers
Aliases	MINDY1, FAM63A, MINDY lysine 48 deubiquitinase 1, MINDY-1
External IDs	OMIM: 618407 MGI: 1922257 HomoloGene: 32409 GeneCards: MINDY1
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q21.3 Start 150,996,086 bp[1] End 151,008,375 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3|3 F2.1 Start 95,281,345 bp[2] End 95,296,166 bp[2]
Gene ontology Molecular function • GO:0001948 protein binding • cysteine-type carboxypeptidase activity • thiol-dependent ubiquitin-specific protease activity • peptidase activity • cysteine-type peptidase activity • hydrolase activity • Lys48-specific deubiquitinase activity • K48-linked polyubiquitin modification-dependent protein binding Cellular component • cell nucleus • nucleoplasm • nuclear body • cytosol Biological process • protein K48-linked deubiquitination • proteolysis • biological process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	55793	75007
Ensembl	ENSG00000143409	ENSMUSG00000038712
UniProt	Q8N5J2	Q76LS9
RefSeq (mRNA)	NM_001040217 NM_001163258 NM_001163259 NM_001163260 NM_018379 NM_001319998 NM_001376664 NM_001376665 NM_001376666 NM_001376667 NM_001376668 NM_001376669 NM_001376670 NM_001376671 NM_001376672 NM_001376673 NM_001376674	NM_133858 NM_199475
RefSeq (protein)	NP_001035307 NP_001156730 NP_001156731 NP_001156732 NP_001306927 NP_060849 NP_001363593 NP_001363594 NP_001363595 NP_001363596 NP_001363597 NP_001363598 NP_001363599 NP_001363600 NP_001363601 NP_001363602 NP_001363603	NP_598619 NP_955769
Location (UCSC)	Chr 1: 151 – 151.01 Mb	Chr 3: 95.28 – 95.3 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Evolutionarily, FAM63A orthologs are found in most vertebrates, and distant homologs of FAM63A are found in invertebrates.[6] FAM63A is ubiquitously expressed throughout human tissues, and it is present during every stage of development.[7]

It has been linked to a biomarker in Chronic Kidney Disease and Alzheimer's Disease.[8]

Gene

Locus

FAM63A is located on the minus strand of chromosome 1 at band 1q21.3, spanning 11,829 bp. Other genes surrounding FAM63A include ANXA9 and Prune.[9]

Aliases

FAM63A has two aliases KIAA1390 and PR11-316M1.5.[10]

mRNA

Primary structure

In humans, there are four isoforms of FAM63A, and there are 10 predicted isoforms. Isoform 1 of FAM63A has a molecular weight of 51.8 kilodaltons, and it contains 11 exons.[11][12] The different isoforms tend to differ at the 5' or 3' end by truncation. Transcription produces 23 introns, 14 spliced variants, and 6 unspliced forms.[13]

Protein

Multiple sequence alignment of DUF demonstrating conservation across orthologs. Dark blue indicates complete conservation, pink identical residues, and light blue chemical similarity

This is a 3D depiction of the probable secondary structure of FAM63A.

Domains and motifs

FAM63A contains a domain of unknown function (DUF 544). DUF544 contains 125 amino acids, running from Met143 to Thr267.[14] Although not completely conserved, this domain is highly conserved across vertebrates, invertebrates, and plants.[15] FAM63A does not contain a transmembrane domain, and it is found primarily in nuclear regions of the cell. [16]

Two repeats of four glutamines are seen from amino acid 400-403 and from amino acid 426-429, leading to an elevated glutamine composition at the C-terminus.

Composition

FAM63A is composed of 469 amino acids.[17] There is an increased presence of glutamine found near the C terminus making FAM63A glutamine rich. FAM63A contains a greater amount of negatively charged (acidic) amino acids than positively charged (basic) amino acids which makes FAM63A a slightly acidic protein. Acidic amino acids such as aspartic acid and glutamic acid are more prevalent than the basic amino acids such as lysine and arginine. This overall acidic composition gives FAM63A an acidic isoelectric point of 4.6.[18]

Post-translational modifications

FAM63A contains 25 phosphorylation sites in humans, including 12 serine, 10 threonine, and 3 tyrosine. Additionally, there are 5 N-myristoylation sites, and there is 1 prenylation site. FAM63A contains no glycosylation sites, transmembrane domains, or signal peptides. [19]

This is a depiction of the posttranslational modifications in FAM63A.

Secondary structure

The secondary structure for FAM63A has not been explicitly determined. There are, however, predictions for a possible secondary structure. There is a coiled-coil domain at the end of the protein, and in the predicted secondary structure, there is an alpha helix between amino acids 410 and 436. This helix is conserved throughout more distant orthologs of FAM63A. These data support each other, and it gives a confident prediction of the secondary structure.[20]

Interacting proteins

The following genes have interactions with FAM63A: GSPT2, NAA38, RNMT, CSNIK1G2, ACOX1, PSMC1, SLC25A37, MMS19, DIAPH1, ME1, GAPDH, UBC. [21] After performing a yeast two-hybrid screen, it was found that NAA38 and FAM63A interact.[22]

Homology/evolution

In FAM63A, there are several amino acids that are conserved in all vertebrates for which sequences are available. Gly239 is the only amino acid that is conserved in all vertebrates, invertebrates, and plants for which sequences are available. Because there is only one amino acid that is absolutely conserved, a possible function for the conserved Glycine was not deduced. The 25 amino acid sequence ranging from Val313 to Gly338 is the most highly conserved in all vertebrates, invertebrates, and plants for which sequences are available. Although the sequence is not absolutely conserved, it is very highly conserved, even in the most distantly related organisms like fungi and plants.

Orthologs

The protein FAM63A has several strict orthologs. These strict orthologs are found in organisms ranging from Primates to Fish.[23]

Scientific Name	Common Name	Divergence	Accession Number	Length	Identity	Similarity	Query Cover
Homo sapiens	Humans	N/A	NP_060849.2	469 aa	100%	100%	100%
Pan paniscus	Bonobo	6.1 MYA	XP_003817322.1	469 aa	99.1%	99.4%	100%
Mus musculus	House Mouse	91.0 MYA	NP_955769.1	468 aa	86.0%	90.2%	100%
Bos taurus	Cow	97.4 MYA	NP_001039389.1	469 aa	85.6%	88.5%	100%
Trichechus manatus latirostris	West Indian Manatee	104.7 MYA	XP_004389621.1	465 aa	84.9%	89.8%	100%
Sarcophilus harrisii	Tasmanian Devil	176.1 MYA	XP_003769968.1	464 aa	78.3%	82.9%	100%
Taeniopygia guttata	Zebra Finch	324.0 MYA	XP_002191502.2	335 aa	43.2%	80.1%	53%
Gallus gallus	Chicken	324.5 MYA	XP_003642724	462 aa	66.9%	76.1%	92%
Chrysemys picta bellii	Painted Turtle	324.5 MYA	XP_005293753.1	525 aa	62.0%	87.2%	78%
Pelodiscus sinensis	Chinese Softshell Turtle	324.5 MYA	XP_006119467.1	502 aa	61.6%	77.4%	94%
Alligator mississippiensis	American Alligator	324.5 MYA	XP_006274676.1	520 aa	59.90%	77.50%	86%
Pseudopodoces humilis	Ground Tit	324.5 MYA	XP_005533539.1	502 aa	58.0%	82.3%	78%
Anas platyrhynchos	Mallard	324.5 MYA	XP_005026841.1	415 aa	57.9%	78.6%	83%
Xenopus tropicalis	Western Clawed Frog	361.2 MYA	XP_002937311.1	506 aa	61.3%	83.7%	76%
Latimeria chalumnae	West Indian Ocean Coelacanth	430.0 MYA	XP_006006147.1	513 aa	44.7%	86.9%	55%
Danio rerio	Zebrafish	454.6 MYA	XP_005159508.1	520 aa	52.2%	80.2%	76%

FAM63A evolved through time at a relatively moderate rate.

This shows the protein conservation throughout evolution. FAM63A evolved at a medium rate compared with cytochrome c (fast) and fibrinogen (slow).

Paralogs

The protein FAM63A has only one known paralog: FAM63B. FAM63B is predicted as having a molecular function in the cell.[24] All of the vertebrates for which sequences are available have two copies of the FAM63 gene, both A and B. FAM63A and FAM63B likely split apart around 666 million years ago, as the closest relative to Homo sapiens containing only one FAM63 is a tapeworm, which diverged 666 million years ago.[25]

Sequence Number	Scientific Name	Common Name	Divergence	Accession Number	Length	Identity	Similarity	Query Cover	E-value
protein FAM63B isoform a	Homo sapiens	Human	N/A	NP_001035540.1	621 aa	41.9%	76.7%	68%	2.00E-129

Expression

Promoter

The promoter region contains a number of transcription factors.[26] Those with high scores include estrogen response elements, TATA boxes, glucocoticoid response elements, and Ccaat/enchancer binding proteins. Experimental data reveals that FAM63A expression decreases when the estrogen receptor is not present, suggesting that the estrogen response elements may serve as an important promoter regulatory mechanism for this protein.[27]

Protein expression

FAM63A is a protein that is ubiquitously expressed across human tissues and throughout development. Although FAM63A is expressed ubiquitously, there are certain tissues that have higher levels of expression including the heart, thyroid, ganglia, and blood.[28]

This is a depiction of the expression levels of FAM63A throughout different human tissues.

Clinical significance

Although there is no specific function determined for FAM63A, there are a few researchers who have discovered possible functions. It has been postulated that FAM63A may be associated with renal function and Chronic Kidney Disease.[8]

Figgins, Minster, and Demirci examined 17,343 functional single nucleotide polymorphisms, demonstrating a strong association between Alzheimer's Disease duration and FAM63A.[29] Another gene located on 1q21, CTSS, was also strongly associated with disease duration, the authors believe that there is a strong linkage disequilibrium between the two genes. FAM63A was identified as one of 39 genes exclusively expressed in CML cells, grouped with four other genes believed to function in protein ligation.

References

1. GRCh38: Ensembl release 89: ENSG00000143409 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000038712 - 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. Gene Cards https://www.genecards.org/cgi-bin/carddisp.pl?gene=FAM63A&search=FAM63A
6. National Center for Bioinformation Technology - BLAST http://blast.ncbi.nlm.nih.gov/Blast.cgi
7. Gene Cards https://www.genecards.org/cgi-bin/carddisp.pl?gene=FAM63A&search=FAM63A
8. Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Glazer NL, et al. (May 2010). "New loci associated with kidney function and chronic kidney disease". Nature Genetics. 42 (5): 376–84. doi:10.1038/ng.568. PMC 2997674. PMID 20383146.
9. Gene Cards https://www.genecards.org/cgi-bin/carddisp.pl?gene=FAM63A&search=FAM63A
10. "Ubiquitin carboxyl-terminal hydrolase MINDY-1 isoform 1 [Homo sapiens] - Protein - NCBI".
11. National Center for Bioinformation Technology - Protein https://www.ncbi.nlm.nih.gov/protein/?term=FAM63A%20AND%20homo%20sapiens
12. National Center for Biotechnology Information - AceView - https://www.ncbi.nlm.nih.gov/ieb/research/acembly/av.cgi?db=human&term=FAM63A&submit=Go
13. National Center for Biotechnology Information - AceView - https://www.ncbi.nlm.nih.gov/ieb/research/acembly/av.cgi?db=human&term=FAM63A&submit=Go
14. National Center for Bioinformation Technology - BLAST http://blast.ncbi.nlm.nih.gov/Blast.cgi
15. San Diego Super Computer http://seqtool.sdsc.edu/CGI/BW.cgi#%5B%5D!
16. PSORT II Prediction http://psort.hgc.jp/form2.html
17. San Diego Super Computer - http://seqtool.sdsc.edu/CGI/BW.cgi#%5B%5D!
18. San Diego Super Computer - http://seqtool.sdsc.edu/CGI/BW.cgi#%5B%5D!
19. ExPASy Bioinformatics Resource Portal http://www.expasy.org/proteomics
20. PHYRE2 -
21. Gene Cards https://www.genecards.org/cgi-bin/carddisp.pl?gene=FAM63A&search=FAM63A
22. STRING - Known and Predicted Protein-Protein Interactions http://string-db.org/newstring_cgi/show_network_section.pl
23. National Center for Biotechnology Information - Protein https://www.ncbi.nlm.nih.gov/protein/?term=FAM63A
24. Gene Cards https://www.genecards.org/cgi-bin/carddisp.pl?gene=FAM63B
25. National Center for Biotechnology Information - Protein https://www.ncbi.nlm.nih.gov/protein/?term=FAM63A
26. Genomatrix - ElDorado - Promoter and transcription factors for FAM63A. http://www.genomatix.de/?s=23e6b2edc9ca33fe998f299bafe56b99
27. Estrogen receptor alpha-silenced MCF7 breast cancer cells. Profile: GDS4061/ FAM63A. ncbi.nlm.nih.gov/geo/tools/profiles
28. National Center for Biotechnology Information - GEO Profiles https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS596:221856_s_at
29. Figgins JA, Minster RL, Demirci FY, Dekosky ST, Kamboh MI (June 2009). "Association studies of 22 candidate SNPs with late-onset Alzheimer's disease". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 150B (4): 520–6. doi:10.1002/ajmg.b.30851. PMC 2751631. PMID 18780302.