THAP3 explained

THAP domain-containing protein 3 (THAP3) is a protein that, in Homo sapiens (humans), is encoded by the THAP3 gene.^[1] The THAP3 protein is as known as MGC33488, LOC90326, and THAP domain-containing, apoptosis associated protein 3. This protein contains the Thanatos-associated protein (THAP) domain^[2] and a host-cell factor 1C binding motif.^[3] These domains allow THAP3 to influence a variety of processes, including transcription and neuronal development.^[4] THAP3 is ubiquitously expressed in H. sapiens, though expression is highest in the kidneys.

Gene

The H. sapiens THAP3 gene is a protein-encoding gene that is located on the plus strand of chromosome 1 at cytogenetic location 1p36.31.^[5] It is 10,727 base pairs long, spanning from genomic coordinates 6,624,868-6,635,595. It contains 6 exons.

Expression

In H. sapiens, THAP3 gene is expressed ubiquitously throughout different tissues, and expression is greatest in the kidneys.^[6] It has also been determined that expression of THAP3 tends to be slightly higher in organs located in the abdomen and male and female sexual organs, such as the ovaries, testes, prostate, adrenal gland, spleen, liver, and colon, though expression in the kidneys is 1.4-1.5x higher than those organs. THAP3 mRNA is 1.3x. more abundant in H. sapiens fetal brain tissue than in H. sapiens adult kidney tissue.^[7]

mRNA

Transcription of the THAP3 gene can result in 11 different mRNA variants, of which 8 are alternatively spliced and 3 are unspliced. Variant 1 is the predominant variant and encodes THAP3 protein isoform 1.

Alternatively spliced Homo sapiens THAP3 mRNA transcript variants^[8] !Variant!Sequence length (nucleotides)!Accession number

1	1358	NM_001195752.2^[9]
2	2071	NM_138350.4^[10]
3	1361	NM_001195753.2^[11]
4	1262	NM_001394496.1^[12]
5	2050	NM_001394497.1^[13]
6	2047	NM_001394498.1^[14]
7	1123	NM_001394499.1^[15]
8	1120	NM_001394500.1^[16]

Protein

The H. sapiens THAP3 protein is predicted to have a molecular weight of 26.9 kilodaltons^[17] and a pI of 10.26.^[18] The amino acid sequence is isoleucine and tyrosine rich and arginine poor. Characteristics domains of H. sapiens are the THAP domain (THAP) and the hell-cell factor 1C binding motif (HCM).

Isoforms

Due to having 8 alternatively spliced variants, there are 8 THAP3 isoforms.

Isoforms of Homo sapiens THAP3!Isoform!Sequence length (amino acids)!Accession number!Encoded by

1	238	NP_001182681.1^[19]	Variant 1
2	175	NP_612359.2^[20]	Variant 2
3	239	NP_001182682.1^[21]	Variant 3
4	236	NP_001381425.1^[22]	Variant 4
5	168	NP_001381426.1^[23]	Variant 5
6	167	NP_001381427.1^[24]	Variant 6
7	148	NP_001381428.1^[25]	Variant 7
8	147	NP_001381429.1^[26]	Variant 8

Structure

The predicted H. sapiens THAP3 tertiary structure contains a globular region and an alpha helix. The globular region is located near the N-terminus of the sequence and is the structure of the THAP domain. It spans amino acids 4-82.^[27] The alpha helix is located from amino acids 186-230 and contains the host-cell factor 1C binding motif.

Regulation

Localization

THAP3 can be localized in the nucleus or mitochondria of H. sapiens cells.^[28]

Post-translation modifications

The H. sapiens the THAP3 protein has 30 predicted phosphorylation sites, 28 predicted O-β-glycosylation sites, and 11 predicted Yin-Yang sites. Many proteins involved in transcription regulation are influenced by phosphorylation and glycosylation sites, which corroborates THAP3's function.^[29]

Homology and evolution

Paralogs

The H. sapiens THAP3 protein, along with several other proteins, is part of the THAP family of proteins.^[30] All of these proteins contain the THAP domain and are, thus, paralogs of H. sapiens THAP3.

Paralogs of Homo sapiens THAP3 protein!Protein Name!E-Value!!Percent Identity to THAP3

THAP1^[31]	8×10^−23	48.00
THAP2^[32]	6×10^−17	45.24
THAP5^[33]	4×10^−13	31.96
THAP6^[34]	6×10^−6	34.44
THAP7^[35]	1×10^−7	33.33
THAP8^[36]	8×10^−11	31.96
THAP9^[37]	2×10^−8	32.99

Orthologs

There are approximately 206 orthlologs of H. sapiens THAP3. Orthologs can be found in a variety of taxomonic classes, including mammals, reptiles, amphibians, bony fishes, and cartilaginous fishes. However, there are no orthologs in bacteria, fungi, protists, archaea, plants, invertebrates, or birds. Additionally, not all orders are represented with in a class. For example, in reptiles, orthologs to H. sapiens THAP3 are found in testudines (turtles or tortoises) and not found in crocodilia (crocodiles and alligators) or squamata (lizards and snakes). Similarly, there are only orthologs in apoda within amphibians. There are no orthologs in anura (frogs) or urodela (salamanders).

In closely related organisms, those diverged 0-160 million years ago (MYA), percent similarity of orthologs ranges from 36-82.9%. THAP3 sequences in rodents are the least conserved compared to H. sapiens. Sequences that diverged 319-353 MYA, those moderately related, have 47.2-68.9% similarity to H. sapiens THAP3, and 41.3-54.1% similarity in organisms that are distantly related, diverged 431-464 MYA.

Date of Divergence^[38]

Accession Number	Percent Identity to THAP3	Percent Similarity to THAP3^[39]
Mammals	Marmota flaviventris	Yellow-bellied marmot	Rodentia	87	XP_027803226.1^[40]	29.9	36
	Lontra canadensis	North American river otter	Carnivora	94	XP_032719186.1^[41]	59.5	65.8
	Eptesicus fuscus	Big brown bat	Chiroptera	94	XP_028016747.1^[42]	65.0	69.6
	Balaenoptera musculus	Blue whale	Cetacea	94	XP_036686252.1^[43]	77.5	82.9
	Dromiciops gliroides	Colocolo opossum	Microbiotheria	160	XP_043850206.1^[44]	64.6	74.5
	Phascolarctos cinereus	Koala	Diprotodontia	160	XP_020830574.1^[45]	65.7	76.4
Reptiles	Caretta caretta	Loggerhead turtle	Testudines	319	XP_048680971.1^[46]	36.9	47.2
	Gopherus evgoodei	Goode's thornscrub tortoise	Testudines	319	XP_030393185.1^[47]	48.9	58.1
	Chelonoidis abingdonii	Abingdon Island giant tortoise	Testudines	319	XP_032619750.1^[48]	48.9	61.4
	Mauremys mutica	Yellow pond turtle	Testudines	319	XP_044852367.1^[49]	49.0	60.9
Amphibians	Microcaecilia unicolor	Microcaecilia unicolor	Gymnophiona	353	XP_030041702.1^[50]	41.2	56.8
	Geotrypetes seraphini	Gaboon caecilian	Gymnophiona	353	XP_033777236.1^[51]	44.2	57.8
Bony Fishes	Electrophorus electricus	Electric eel	Gymnotiformes	431	XP_026873261.2^[52]	31.9	41.3
	Coregonus clupeaformis	Lake whitefish	Salmoniformes	431	XP_041712304.2^[53]	32.9	47.7
	Brienomyrus brachyistius	Baby whale	Osteoglossiformes	431	XP_048872538.1^[54]	33.5	46.3
	Puntigrus tetrazona	Sumatra barb	Cypriniformes	431	XP_043081346.1^[55]	34.0	48.1
Cartilaginous Fishes	Rhincodon typus	Whale shark	Orectolobiformes	464	XP_020386430.1^[56]	39.0	53.4
	Chiloscyllium plagiosum	White-spotted bamboo shark	Orectolobiformes	464	XP_043531920.1^[57]	39.0	53.0
	Amblyraja radiata	Thorny skate	Rajiformes	464	XP_032904038.1^[58]	40.2	54.1

Evolution

H. sapiens THAP3 has evolved at a rate similar to H. sapiens fibrinogen alpha, which is involved in the immune system.

Protein interactions

H. sapiens THAP3 interacts with proteins involved in various cellular processes, like transcription regulation and neuronal development. It is also interacts with molecular chaperones during its translation.

Identified By!^[59]

Interaction Type
Transcription Regulation	CHAT	two hybrid assay	Functional
	FGFR3	two hybrid assay	Functional
	HCF1C^[60]	affinity capture - mass spectrometry	Functional
	OGT	affinity capture - mass spectrometry	Functional
	PKN1	two hybrid assay	Functional
	POLR2A	two hybrid assay	Functional
	TARDBP	two hybrid assay	Functional
Neuronal Development	LSAMP	two hybrid assay	Functional
	DNAJB6	two hybrid assay	Functional
Protein Folding	BAG6	two hybrid assay	Developmental

Clinical significance

THAP3 contributes to the presentation of X-linked Dystonia-Parkinsonism, also known as Lubag Syndrome.^[61] This disease is a neurodegenerative movement disorder that predominantly affects males of Filipino descent.^[62] Symptoms include tremors, bradykinesia, rigidity, postural instability, shuffling gait and dystonia, which typically develops later in life.

Notes and References

1. Web site: THAP3 THAP domain containing 3 [Homo sapiens (human)] - Gene - NCBI ]. 2022-12-08 . www.ncbi.nlm.nih.gov.
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3. Web site: 2022-04-22 . Homo sapiens THAP domain containing 3 (THAP3), transcript variant 1, mRNA . en-US.
4. Sabogal A, Lyubimov AY, Corn JE, Berger JM, Rio DC . THAP proteins target specific DNA sites through bipartite recognition of adjacent major and minor grooves . Nature Structural & Molecular Biology . 17 . 1 . 117–123 . January 2010 . 20010837 . 2933787 . 10.1038/nsmb.1742 .
5. Web site: Entry - *612532 - THAP Doman-Containing Protein 3; THAP3 - OMIM . 2022-12-15 . www.omim.org . en-us.
6. Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, Asplund A, Sjöstedt E, Lundberg E, Szigyarto CA, Skogs M, Takanen JO, Berling H, Tegel H, Mulder J, Nilsson P, Schwenk JM, Lindskog C, Danielsson F, Mardinoglu A, Sivertsson A, von Feilitzen K, Forsberg M, Zwahlen M, Olsson I, Navani S, Huss M, Nielsen J, Ponten F, Uhlén M . 6 . Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics . Molecular & Cellular Proteomics . 13 . 2 . 397–406 . February 2014 . 24309898 . 3916642 . 10.1074/mcp.M113.035600 . free .
7. Duff MO, Olson S, Wei X, Garrett SC, Osman A, Bolisetty M, Plocik A, Celniker SE, Graveley BR . 6 . Genome-wide identification of zero nucleotide recursive splicing in Drosophila . Nature . 521 . 7552 . 376–379 . May 2015 . 25970244 . 4529404 . 10.1038/nature14475 . 2015Natur.521..376D .
8. Web site: Protein BLAST: search protein databases using a protein query . 2022-12-08 . National Center of Biotechnology Information . en.
9. Web site: April 22, 2022 . Homo sapiens THAP domain containing 3 (THAP3), transcript variant 1, mRNA . NCBI Nucleotide.
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11. 10 June 2022 . Homo sapiens THAP domain containing 3 (THAP3), transcript variant 3, m - Nucleotide - NCBI . www.ncbi.nlm.nih.gov.
12. Web site: April 22, 2022 . Homo sapiens THAP domain containing 3 (THAP3), transcript variant 4, mRNA . NCBI Nucleotide.
13. Web site: April 22, 2022 . Homo sapiens THAP domain containing 3 (THAP3), transcript variant 5, mRNA . NCBI Nucleotide.
14. Web site: April 22, 2022 . Homo sapiens THAP domain containing 3 (THAP3), transcript variant 6, mRNA . NCBI Nucleotide.
15. 22 April 2022 . Homo sapiens THAP domain containing 3 (THAP3), transcript variant 7, m - Nucleotide - NCBI . www.ncbi.nlm.nih.gov.
16. Web site: April 22, 2022 . Homo sapiens THAP domain containing 3 (THAP3), transcript variant 8, mRNA . NCBI Nucleotide.
17. Brendel V, Bucher P, Nourbakhsh IR, Blaisdell BE, Karlin S . Methods and algorithms for statistical analysis of protein sequences . Proceedings of the National Academy of Sciences of the United States of America . 89 . 6 . 2002–2006 . March 1992 . 1549558 . 48584 . 10.1073/pnas.89.6.2002 . free . 1992PNAS...89.2002B .
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19. Web site: THAP domain-containing protein 3 isoform 1 [Homo sapiens] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
20. Web site: THAP domain-containing protein 3 isoform 2 [Homo sapiens] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
21. Web site: THAP domain-containing protein 3 isoform 3 [Homo sapiens] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
22. Web site: THAP domain-containing protein 3 isoform 4 [Homo sapiens] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
23. Web site: THAP domain-containing protein 3 isoform 5 [Homo sapiens] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
24. Web site: THAP domain-containing protein 3 isoform 6 [Homo sapiens] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
25. Web site: THAP domain-containing protein 3 isoform 7 [Homo sapiens] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
26. Web site: THAP domain-containing protein 3 isoform 8 [Homo sapiens] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
27. Wang J, Youkharibache P, Marchler-Bauer A, Lanczycki C, Zhang D, Lu S, Madej T, Marchler GH, Cheng T, Chong LC, Zhao S, Yang K, Lin J, Cheng Z, Dunn R, Malkaram SA, Tai CH, Enoma D, Busby B, Johnson NL, Tabaro F, Song G, Ge Y . 6 . iCn3D: From Web-Based 3D Viewer to Structural Analysis Tool in Batch Mode . Frontiers in Molecular Biosciences . 9 . 831740 . 2022 . 35252351 . 8892267 . 10.3389/fmolb.2022.831740 . free .
28. Web site: PSORT II Prediction . 2022-12-16 . psort.hgc.jp.
29. Filtz TM, Vogel WK, Leid M . Regulation of transcription factor activity by interconnected post-translational modifications . Trends in Pharmacological Sciences . 35 . 2 . 76–85 . February 2014 . 24388790 . 3954851 . 10.1016/j.tips.2013.11.005 .
30. Sanghavi HM, Mallajosyula SS, Majumdar S . Classification of the human THAP protein family identifies an evolutionarily conserved coiled coil region . BMC Structural Biology . 19 . 1 . 4 . March 2019 . 30836974 . 6402169 . 10.1186/s12900-019-0102-2 . free .
31. Web site: THAP1 THAP domain containing 1 [Homo sapiens (human)] - Gene - NCBI ]. National Center of Biotechnology Information.
32. Web site: THAP2 THAP domain containing 2 [Homo sapiens (human)] - Gene - NCBI ]. National Center of Biotechnology Information.
33. Web site: THAP5 THAP domain containing 5 [Homo sapiens (human)] - Gene - NCBI ]. National Center of Biotechnology Information.
34. Web site: THAP6 THAP domain containing 6 [Homo sapiens (human)] - Gene - NCBI ]. National Center of Biotechnology Information.
35. Web site: THAP7 THAP domain containing 7 [Homo sapiens (human)] - Gene - NCBI ]. National Center of Biotechnology Information.
36. Web site: THAP8 THAP domain containing 8 [Homo sapiens (human)] - Gene - NCBI ]. National Center of Biotechnology Information.
37. Web site: THAP9 THAP domain containing 9 [Homo sapiens (human)] - Gene - NCBI ]. National Center of Biotechnology Information.
38. 6 . Kumar S, Suleski M, Craig JM, Kasprowicz AE, Sanderford M, Li M, Stecher G, Hedges SB . August 2022 . TimeTree 5: An Expanded Resource for Species Divergence Times . Molecular Biology and Evolution . 39 . 8 . msac174 . 10.1093/molbev/msac174 . 9400175 . 35932227.
39. Web site: EMBOSS Needle < Pairwise Sequence Alignment < EMBL-EBI . 2022-12-08 . www.ebi.ac.uk.
40. Web site: THAP domain-containing protein 3 isoform X1 [Marmota flaviventris] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
41. Web site: THAP domain-containing protein 3 isoform X1 [Lontra canadensis] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
42. Web site: THAP domain-containing protein 3 isoform X1 [Eptesicus fuscus] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
43. Web site: THAP domain-containing protein 3 isoform X1 [Balaenoptera musculus] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
44. Web site: THAP domain-containing protein 3 isoform X1 [Dromiciops gliroides] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
45. Web site: THAP domain-containing protein 3 isoform X1 [Phascolarctos cinereus] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
46. Web site: THAP domain-containing protein 3 isoform X1 [Caretta caretta] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
47. Web site: THAP domain-containing protein 3 isoform X1 [Gopherus evgoodei] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
48. Web site: THAP domain-containing protein 3 isoform X1 [Chelonoidis abingdonii] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
49. Web site: THAP domain-containing protein 3 isoform X1 [Mauremys mutica] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
50. Web site: THAP domain-containing protein 3 isoform X1 [Microcaecilia unicolor] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
51. Web site: THAP domain-containing protein 3 isoform X1 [Geotrypetes seraphini] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
52. Web site: THAP domain-containing protein 3 isoform X1 [Electrophorus electricus] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
53. Web site: THAP domain-containing protein 3 isoform X1 [Coregonus clupeaformis] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
54. Web site: THAP domain-containing protein 3 isoform X1 [Brienomyrus brachyistius] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
55. Web site: THAP domain-containing protein 3 isoform X1 [Puntigrus tetrazona] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
56. Web site: THAP domain-containing protein 3 isoform X1 [Rhincodon typus] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
57. Web site: THAP domain-containing protein 3 isoform X1 [Chiloscyllium plagiosum] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
58. Web site: THAP domain-containing protein 3 isoform X1 [Amblyraja radiata] - Protein - NCBI]. www.ncbi.nlm.nih.gov.
59. Web site: IntAct Portal . 2022-12-16 . www.ebi.ac.uk.
60. Web site: THAP3 Result Summary BioGRID . 2022-12-16 . thebiogrid.org.
61. Web site: THAP3 Gene - GeneCards THAP3 Protein THAP3 Antibody . 2022-12-08 . www.genecards.org.
62. Rosales RL . X-linked dystonia parkinsonism: clinical phenotype, genetics and therapeutics . English . Journal of Movement Disorders . 3 . 2 . 32–38 . October 2010 . 24868378 . 4027667 . 10.14802/jmd.10009 .