THAP3

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File:Homo sapiens THAP3 Tertiary Structure.png
Predicted Tertiary Structure of Homo sapiens THAP3 protein.[1][2]

THAP domain-containing protein 3 (THAP3) is a protein that, in Homo sapiens (humans), is encoded by the THAP3 gene.[3] 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[4] and a host-cell factor 1C binding motif.[5] These domains allow THAP3 to influence a variety of processes, including transcription and neuronal development.[6] THAP3 is ubiquitously expressed in H. sapiens, though expression is highest in the kidneys.[3]

Gene

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The H. sapiens THAP3 gene is a protein-encoding gene that is located on the plus strand of chromosome 1[3] at cytogenetic location 1p36.31.[7] It is 10,727 base pairs long, spanning from genomic coordinates 6,624,868-6,635,595.[7] It contains 6 exons.[8]

File:Gene Neighborhood of Homo sapiens THAP3.png
Gene neighborhood of Homo sapiens (human) THAP3 gene on chromosome 1.[3]

Expression

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In H. sapiens, THAP3 gene is expressed ubiquitously throughout different tissues, and expression is greatest in the kidneys.[9] 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.[9] THAP3 mRNA is 1.3x. more abundant in H. sapiens fetal brain tissue than in H. sapiens adult kidney tissue.[10]

mRNA

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

Alternatively spliced Homo sapiens THAP3 mRNA transcript variants[11]
Variant Sequence length (nucleotides) Accession number[3]
1 1358 NM_001195752.2[12]
2 2071 NM_138350.4[13]
3 1361 NM_001195753.2[14]
4 1262 NM_001394496.1[15]
5 2050 NM_001394497.1[16]
6 2047 NM_001394498.1[17]
7 1123 NM_001394499.1[18]
8 1120 NM_001394500.1[19]

Protein

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File:Conceptual Translation of Homo sapiens THAP3.png
Conceptual translation of Homo sapiens THAP3 aligned mRNA and amino acid sequences. Annotated with start and stop sites of translations, protein domains, and predicted post-translational modification sites.

The H. sapiens THAP3 protein is predicted to have a molecular weight of 26.9 kilodaltons[20] and a pI of 10.26.[21] The amino acid sequence is isoleucine and tyrosine rich and arginine poor.[20] Characteristics domains of H. sapiens are the THAP domain (THAP) and the hell-cell factor 1C binding motif (HCM).[3]

Isoforms

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Due to having 8 alternatively spliced variants, there are 8 THAP3 isoforms.[3]

Isoforms of Homo sapiens THAP3[3]
Isoform Sequence length (amino acids) Accession number Encoded by
1 238 NP_001182681.1[22] Variant 1
2 175 NP_612359.2[23] Variant 2
3 239 NP_001182682.1[24] Variant 3
4 236 NP_001381425.1[25] Variant 4
5 168 NP_001381426.1[26] Variant 5
6 167 NP_001381427.1[27] Variant 6
7 148 NP_001381428.1[28] Variant 7
8 147 NP_001381429.1[29] Variant 8

Structure

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File:Cartoon Schematic of Homo sapiens THAP3.png
Schematic of Homo sapiens THAP3 protein sequence with annotated domains, predicted phosphorylation, glycosylation, and Yin-Yang sites.[30] THAP represents the location of the THAP domain, and HBM represents the HCF1C binding motif. Yellow represents glycosylation sites (with scores over 0.5),[31] green represents phosphorylation sites (with scores over 0.75),[32] and diamond shapes represent Yin-Yang sites.[31]

The predicted H. sapiens THAP3 tertiary structure contains a globular region and an alpha helix.[1][2] 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.[33] The alpha helix is located from amino acids 186-230 and contains the host-cell factor 1C binding motif.[33]

Regulation

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Localization

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THAP3 can be localized in the nucleus or mitochondria of H. sapiens cells.[34]

Post-translation modifications

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The H. sapiens the THAP3 protein has 30 predicted phosphorylation sites, 28 predicted O-β-glycosylation sites, and 11 predicted Yin-Yang sites.[31][32] Many proteins involved in transcription regulation are influenced by phosphorylation and glycosylation sites, which corroborates THAP3's function.[35]

Homology and evolution

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Paralogs

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The H. sapiens THAP3 protein, along with several other proteins, is part of the THAP family of proteins.[36] All of these proteins contain the THAP domain and are, thus, paralogs of H. sapiens THAP3.[11]

Paralogs of Homo sapiens THAP3 protein[3]
Protein Name E-Value![11] Percent identity to THAP3[11]
THAP1[37] 8×10−23 48.00
THAP2[38] 6×10−17 45.24
THAP5[39] 4×10−13 31.96
THAP6[40] 6×10−6 34.44
THAP7[41] 1×10−7 33.33
THAP8[42] 8×10−11 31.96
THAP9[43] 2×10−8 32.99

Orthologs

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File:MSA of THAP3.png
Multiple sequence alignment of THAP domain in Homo sapiens THAP3 (HSa THAP3; accession number NP 001182681.1[8]) with distant orthologs.[44] Boxing represents the location of the THAP domain in H. sapiens. Bolding and asterisks below groups of sequence indicate that an amino acid is highly conserved at that position. Full sequences include that of Sumatra barb (PTe THAP3), Electric eel (EEl THAP3), Lake whitefish (CCL THAP3), Baby whale (BBr THAP3), Whale shark (ARa THAP3), White-spotted bamboo shark (RTy THAP3), and Thorny skate (CPl THAP3). Accession numbers as in ortholog table.

There are approximately 206 orthlologs of H. sapiens THAP3.[3] Orthologs can be found in a variety of taxomonic classes, including mammals, reptiles, amphibians, bony fishes, and cartilaginous fishes.[11] However, there are no orthologs in bacteria, fungi, protists, archaea, plants, invertebrates, or birds.[11] 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).[11] Similarly, there are only orthologs in apoda within amphibians.[11] There are no orthologs in anura (frogs) or urodela (salamanders).[11]

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.

Orthologs of Homo sapiens THAP3[45]
Taxonomic Class Scientific Name Common Name Taxonomic Order Date of Divergence[46] Accession Number[11] Percent Identity to THAP3 Percent Similarity to THAP3[47]
Mammals Marmota flaviventris Yellow-bellied marmot Rodentia 87 XP_027803226.1[48] 29.9 36
Lontra canadensis North American river otter Carnivora 94 XP_032719186.1[49] 59.5 65.8
Eptesicus fuscus Big brown bat Chiroptera 94 XP_028016747.1[50] 65.0 69.6
Balaenoptera musculus Blue whale Cetacea 94 XP_036686252.1[51] 77.5 82.9
Dromiciops gliroides Colocolo opossum Microbiotheria 160 XP_043850206.1[52] 64.6 74.5
Phascolarctos cinereus Koala Diprotodontia 160 XP_020830574.1[53] 65.7 76.4
Reptiles Caretta caretta Loggerhead turtle Testudines 319 XP_048680971.1[54] 36.9 47.2
Gopherus evgoodei Goode's thornscrub tortoise Testudines 319 XP_030393185.1[55] 48.9 58.1
Chelonoidis abingdonii Abingdon Island giant tortoise Testudines 319 XP_032619750.1[56] 48.9 61.4
Mauremys mutica Yellow pond turtle Testudines 319 XP_044852367.1[57] 49.0 60.9
Amphibians Microcaecilia unicolor Microcaecilia unicolor Gymnophiona 353 XP_030041702.1[58] 41.2 56.8
Geotrypetes seraphini Gaboon caecilian Gymnophiona 353 XP_033777236.1[59] 44.2 57.8
Bony Fishes Electrophorus electricus Electric eel Gymnotiformes 431 XP_026873261.2[60] 31.9 41.3
Coregonus clupeaformis Lake whitefish Salmoniformes 431 XP_041712304.2[61] 32.9 47.7
Brienomyrus brachyistius Baby whale Osteoglossiformes 431 XP_048872538.1[62] 33.5 46.3
Puntigrus tetrazona Sumatra barb Cypriniformes 431 XP_043081346.1[63] 34.0 48.1
Cartilaginous Fishes Rhincodon typus Whale shark Orectolobiformes 464 XP_020386430.1[64] 39.0 53.4
Chiloscyllium plagiosum White-spotted bamboo shark Orectolobiformes 464 XP_043531920.1[65] 39.0 53.0
Amblyraja radiata Thorny skate Rajiformes 464 XP_032904038.1[66] 40.2 54.1

Evolution

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H. sapiens THAP3 has evolved at a rate similar to H. sapiens fibrinogen alpha, which is involved in the immune system.[11]

Protein interactions

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H. sapiens THAP3 interacts with proteins involved in various cellular processes, like transcription regulation and neuronal development.[6] It is also interacts with molecular chaperones during its translation.

Homo sapiens THAP3 Protein Interactions[67]
Process Protein Name Identified By![68] Interaction Type
Transcription Regulation CHAT two hybrid assay Functional
FGFR3 two hybrid assay Functional
HCF1C[69] affinity capture - mass spectrometry Functional
OGT[69] 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

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THAP3 contributes to the presentation of X-linked Dystonia-Parkinsonism, also known as Lubag Syndrome.[70] This disease is a neurodegenerative movement disorder that predominantly affects males of Filipino descent.[71] Symptoms include tremors, bradykinesia, rigidity, postural instability, shuffling gait and dystonia, which typically develops later in life.[71]

References

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