Tetratricopeptide repeat protein 39B is a protein that in humans is encoded by the TTC39B gene. TTC39B is also known as C9orf52 or FLJ33868. The main feature within tetratricopeptide repeat 39B is the domain of unknown function 3808 (DUF3808), spanning the majority of the protein.

Gene

The gene for TTC39B is located on the short arm of the ninth chromosome at 9p22.3. The genomic DNA is 136,517 bases long, consists of 39 introns and 20 exons, and is on the minus strand. The mRNA has a length of 3,276 bases. TTC39B is surrounded by LOC100419056, a chloride channel, voltage-sensitive 3 pseudogene.

Function

TTC39B is expected to have a molecular binding function as well as a role in lipid regulation; the phenotype as well as the function in vivo is unknown.

Homology and evolution

Paralogs

There are two known paralogs for TTC39B: TTC39A and TTC39C. TTC39A has two splice isoforms and TTC39C has three splice isoforms.

TTC39A has been tested for association to diseases like breast neoplasms and is expected to have molecular binding function and localizes in various compartments (extracellular space, membrane, nucleus).

TTC39C is expected to localize in cytoplasm. No phenotype has been discovered, and the gene's in vivo function is unknown.

Orthologs

Genus and species Common name RNA Percent Identity Divergence Pan paniscus Bonobo 99% 6.3 MYA Pan troglodytes Chimpanzee 99% 6.3 MYA Gorilla gorilla gorilla Gorilla 99% 8.8 MYA Nomascus leucogenys Gibbon 98% 20.4 MYA Papio anubis Baboon 97% 29.0 MYA Pongo pygmaeus Orangutan 97% 15.7 MYA Callithrix jacchus Marmoset 96% 42.6 MYA Saimiri boliviensis boliviensis Squirrel monkey 94% 42.6 MYA Canis lupus familiaris Dog 91% 94.2 MYA Otolemur garnettii Bushbaby 90% 74.0 MYA Felis catus Cat 89% 94.2 MYA Bos taurus Cow 88% 94.2 MYA Cricetulus griseus Hamster 87% 92.3 MYA Ovis aries Sheep 85% 94.2 MYA Rattus norvegicus Rat 85% 92.3 MYA

Distant homologs

Genus and species Common name RNA Percent Identity Divergence Sarcophilus harrisii Tasmanian devil 78% 162.6 MYA Gallus gallus Chicken 75% 296.0 MYA Taeniopygia guttata Zebra finch 75% 296.0 MYA Anolis carolinensis Lizard 75% 296.0 MYA Xenopus laevis Frog 74% 371.2 MYA

Phylogeny

TTC39B is conserved in organisms from human to platyhelminthes and is not conserved in yeast and fungi.

Protein

The TTC39B gene has five different transcript variants, each coding for a different protein. This article focuses on tetratricopeptide repeat protein 39B isoform 1, the longest of all of the proteins. When translated, the TTC39B protein is composed of 682 amino acids and has a molecular weight of 76,955.64 kDa. The isoelectric point of the protein is 7.16 pH.

Conservation

Close Orthologs: Genus and species Common name Protein Percent Identity Divergence Pan troglodytes Chimpanzee 99% 6.3 MYA Pan paniscus Bonobo 99% 6.3 MYA Nomascus leucogenys Gibbon 98% 20.4 MYA Papio anubis Baboon 98% 29.0 MYA Callithrix jacchus Marmoset 97% 42.6 MYA Saimiri boliviensis boliviensis Squirrel monkey 96% 42.6 MYA Heterocephalus glaber Naked mole-rat 92% 92.3 MYA Canis lupus familiaris Dog 91% 94.2 MYA Cricetulus griseus Hamster 90% 92.3 MYA Ovis aries Sheep 89% 94.2 MYA Cavia porcellus Guinea pig 86% 92.3 MYA

Distant Orthologs:

Genus and species Common name Protein Percent Identity Divergence Sarcophilus harrisii Tasmanian devil 73% 162.6 MYATaeniopygia guttata Zebra finch 72% 296.0 MYAPteropus alecto Bat 55% 94.2 MYABos taurus Cow 54% 94.2 MYARattus norvegicus Rat 54% 92.3 MYAGallus gallus Chicken 54% 296.0 MYADanio rerio Zebrafish 54% 400.1 MYACrassostrea gigas Oyster 50% 782.7 MYA Camponotus floridanus Ant 43% 782.7 MYANasonia vitripennis Wasp 42% 782.7 MYACiona intestinalis Urochordata 40% 722.5 MYAClonorchis sinensis Liver fluke 35% 792.4 MYA

Domains and motifs

The Domain of Unknown Function 3808 (DUF3808) domain is conserved from fungi to humans and is currently has an unknown function. It is located from amino acid 142 until 568 (a length of 427 amino acids). Proteins of this family also contain a TPR_2 domain at their C-terminus, which also has an unknown function.

Another conserved domain in the TTC39B protein is the TPR_12 tetratricopeptide repeat. It is located from amino acid 600 until 658 (a length of 59 amino acids). The TPR domains are found in many proteins that facilitate specific interactions with a partner protein. Three-dimensional structural data have shown that a TPR region forms two antiparallel alpha-helices. TPR motifs that are arranged one in front of another create a right-handed helical structure with an amphipathic channel which could possibly accommodate the complementary region of a target protein. Most TPR-containing proteins are associated with multiprotein complexes, and there is extensive evidence indicating that TPR motifs are important to the functioning of chaperone, cell-cycle, transcription, and protein transport complexes. Two more TPR domains are found in the TTC39B protein: TPR1 which spans from amino acids 393 to 426 (34 amino acids long) and TPR2 which spans from amino acids 626 to 659 (also 34 amino acids long).

TTC39B contains three transmembrane regions, all located within the DUF3808 region. Since there are three transmembrane regions, the N-terminus and C-terminus of the protein will be on opposite sides of the plasma membrane.

Post-translational modifications

Phosphorylation Sites:

Amino Acid Position Serine (S) 28, 32, 42, 51, 61, 62, 72, 91, 93, 94, 96, 101, 102, 107, 120, 123, 124, 125, 126, 127, 134, 148, 165, 173, 194, 215, 217, 218, 221, 224, 229, 270, 279, 305, 313, 329, 344, 347, 350, 365, 393, 421, 454, 461, 464, 477, 500, 509, 524, 526, 548, 551, 557, 573, 578, 580, 614, 634, 638, 660, 663, 680, 681 Threonine (T) 89, 100, 110, 121, 128, 152, 174, 183, 202, 211, 250, 269, 356, 362, 370, 467, 487, 493, 512, 563, 628, 651 Tyrosine (Y) 167, 172, 206, 210, 239, 271, 274, 295, 363, 398, 434, 451, 452, 453, 468, 523, 542, 608, 620, 623, 636, 656, 659

Probability of Sumoylation Sites (bolded):

No. Position Group Score 1 619 ESEKL LKYD HYLVP 0.91 2 262 NMINF IKGG LKIRT 0.77 3 302 EFEGG VKLG SGAFN 0.76 4 133 STKVD LKSG LEECA 0.73

There is one possible N-glycosylation site at amino acid 391, however, since the TTC39B protein does not contain a signal peptide, it is unlikely that this glycosylation actually occurs.

Secondary structure

According to an analysis of the secondary protein structure, TTC39B is most likely to be expressed in the endoplasmic reticulum, mitochondria, and Golgi apparatus.

Tertiary and quaternary structure

The TTC39B protein folds into an alpha-alpha super helix. 40% of its structure matches with d1w3ba, the superhelical domain of o-linked GlcNAc transferase. O-GlcNAc couples metabolic status to the regulation of a wide variety of cellular signaling pathways by acting as a nutrient sensor.

Expression

Promoter and transcription start site

The promoter for TTC39B starts at base pair 15,307,109 and ends at base pair 15,307,858. It has a length of 750 base pairs. The transcription start site for TTC39B protein isoform 1 is located from base pairs 15,307,340 to 15,307,389 and has a length of 50 bp.

Expression profile

TTC39B is well expressed in muscles, internal organs, secretory organs, reproductive organs, the immune system, and the nervous system. TTC39B is expressed in a multitude of tissues: testis, lung, islets of langerhans, pancreas, kidney, pooled germ cell tumors, breast carcinoma, etc.

Transcript variants

There are five different transcript variants for the TTC39B gene. Isoform 1 is the longest transcript and encodes the longest isoform. Isoform 2 uses an alternate in-frame splice site in the central coding region, compared to variant 1, which results in a shorter protein. Isoform 3 and 4 have multiple differences in the central coding region but maintain the reading frame compared to isoform 1. Isoform 5 differs in the 5' UTR and has multiple coding region differences, compared to variant 1. These differences cause translation initiation at an in-frame downstream AUG and results in isoform 5 having a shorter N-terminus compared to isoform 1.

Interacting proteins

Binding transcription factors

Transcription Factor Binding Sites: Matrix Family Detailed Family Information From To Strand Similarity Sequence (CAPITALS: core sequence) V$PLAG Pleomorphic adenoma gene 51 73 (+) 1.000 taGGGGgaagtagaggagttcca V$TALE TALE homeodomain class recognizing TG motifs 157 173 (+) 1.000 ggtggtgtGTCAgaggc V$ZF02 C2H2 zinc finger transcription factors 2 294 316 (-) 1.000 cagcgCCCCacctggggtccgtg V$MIZ1 Myc-interacting Zn finger protein 1 417 427 (-) 1.000 cacgcCCTCtg O$TF2B RNA polymerase II transcription factor II B 517 523 (-) 1.000 ccgCGCC

Cellular Proteins

TTC39B interacts with ubiquitin C (UBC), a polyubiquitin precursor. Conjugation of ubiquitin monomers or polymers leads to different effects within a cell. Ubiquitination has been associated with protein degradation, DNA repair, cell cycle regulation, kinase modification, endocytosis, and regulation of other cell signaling pathways.

Clinical significance

Disease association

On a locus on chromosome 9p22 found to be associated with high-density lipoprotein (HDL-C), TTC39B was the only one of several genes in the locus to have an eQTL in liver, with the allele associated with decreased expression correlating with increased HDL-C. Knockdown of the mouse ortholog TTC39B via a viral vector (50% knockdown) resulted in significantly higher plasma HDL-C levels at 4 days and 7 days. The data indicates that TTC39B as causal genes for lipid regulation.

References