TMEM19 explained

Transmembrane protein 19 is a protein that in humans is encoded by the TMEM19 gene.

Gene

The TMEM19 gene is located on chromosome 12(12q21.1) spanning 18,966 base pairs on the + strand. The gene has a total of 6 exon regions.

Studies have found that after using single nucleotide polymorphism (SNP) genotyping array method the TMEM19 gene was identified to be associated with ammonia nitrogen tolerance.^[1] Using a genome-wide association study of individuals with non-syndromic cleft lip with palate (NSCLP) to identify loci that are at risk for the birth defect.^[2] From this they were able to identify the loci of TMEM19 as a risk for this birth defect, along with 25 other loci.

Transcript

The mRNA transcript of TMEM19 is 5662 base pairs. The TMEM19 transcript was found to be expressed in most tissues but has increased expression in duodenum, kidney, skin, small intestine, and urinary bladder. in a non-alcoholic fatty liver disease (NAFLD) model in cells that were subjected to glucose deficiency or oxidative stress. This results in cell death due to excessive disulfide formation in actin cytoskeleton and actin filament called disulfidptosis.^[3]

Protein

TMEM19 is a protein spanning 336 amino acids. It has 6 transmembrane regions. The protein is found at moderate levels in the body, with the highest expression found in superior cervical ganglia and cardiac myocytes.^[4] TMEM19 interacts with many proteins, most of these proteins are localized around membranes found in the cell.

Protein Interactions

Protein	Full Name	Detection Method	Description	CV
MC4R	Melanocortin 4 Receptor	Ubiquitin Reconstruction	Membrane-bound receptor and member of the melanocortin receptor family. Protein interacts with adrenocorticotropic and MSH hormones. Mediated by G proteins. (NCBI^[5])	0.37
BSCL2	Bernardinelli-Seip Congenital Lipodystrophy Type 2 Protein	Two Hybrid	Also known as Seipin, a multi-pass transmembrane protein. Localized in the ER and is predicted to be associated with lipid droplet morphology. Mutations of this gene leads to Berardinelli-Seip syndrome which results in absence of adipose tissue and severe insulin resistance. (NCBI^[6])	0.67
APOA5	Apolipoprotein A5	Two Hybrid	Plays a role in regulating the plasma triglyceride levels, a major risk factor of CAD. Is a component of high-density lipoprotein, similar to a rat protein that is upregulated in response to liver injury. Mutations in the gene are associated with hypertriglyceridemia and hyperlipoproteinemia type 5. (NCBI^[7])	0.56
AQP6	Aquaporin 6	Two Hybrid	Functions as a water channel in cells. Specific to the kidney. (NCBI^[8])	0.56
C10orf67	Chromosome 10 open reading frame 67	Two Hybrid	Predicted to be located in mitochondrion. Possible link to Crohn's and sarcoidosis. (NCBI^[9])	0.56
CD3G	CD3 gamma subunit of T-cell receptor complex	Two Hybrid	Component of the T-cell receptor-CD3 complex. Mutations with this protein are associated with T cell immunodeficieny. (NCBI^[10])	0.56
CD79A	CD79a molecule	Two Hybrid	The Ig-alpha protein of the B-cell antigen component. (NCBI^[11])	0.56
CNR2	Cannabinoid receptor 2	Two Hybrid	G protein-coupled receptor from cannabinoid family. Related to CB1 which is responsible for the efficacy of THC. Mainly expressed in cells of the immune system. (NCBI^[12])	0.56
CPLX4	Complexin 4	Two Hybrid	May be involved in synaptic vesicle exocytosis. (NCBI^[13])	0.56
CREB3	cAMP responsive element binding protein 3	Two Hybrid	Transcription factor that bind to cAMP-response element and regulates cell proliferation. Also plays a role in leukocyte migration, tumor suppression, and ER stress-associated protein degradation. (NCBI^[14])	0.56
CREB3L1	cAMP responsive element binding protein 3 like 1	Two Hybrid	Normally found in the membrane of ER. Upon stress to ER the protein is cleaved and released into the cytoplasm where is translocated to the nucleus. It then activates the transcription of target genes by binding to box-B elements. (NCBI^[15])	0.56

Post translational modifications

Using BioCuckoo, TMEM19 was analyzed for phosphorylation sites in the protein sequence. The program was run on a medium threshold and scanned for every kinase available. Phosphorylation sites are in order of decreasing score. AGC represents protein kinase A, protein kinase G, and protein kinase C.^[16]

Position

Code	Kinase	Protein Sequence Pos.	Score	Cutoff
197	S	AGC	SEVGPVLSKSSPRLI	0.0559	0.0197
214	T	AGC	WEKVPVGTNGGVTVV	0.0568	0.0197
187	T	CK1	LACSAGDTWASEVGP	0.0666	0.0532
108	S	AGC	LMFFLSSSKLTKWKG	0.1333	0.0197
288	T	CK1	YTGLDESTGMVVNSP	0.1427	0.0532
287	S	CK1	QYTGLDESTGMVVNS	0.1517	0.0532
200	S	CDK, MAPK,GSK, CLK	GPVLSKSSPRLITTW	0.1546	0.0403
296	T	CK1	GMVVNSPTNKARHIA	0.2926	0.0532
125	Y	TK	KKRLDSEYKEGGQRN	0.7851	0.7641
167	Y	TK	PVDFSKQYSASWMCL	0.8679	0.7641
281	Y	TK	YLGATMQYTGLDEST	0.9762	0.7641

Evolutionary history

TMEM19 Orthologs were sorted by the median date of divergence. TMEM19 has a median date of divergence greater than 1598 MYA which is found in Thale cress. TMEM19 does not have any paralogs, this was determined after running TMEM19 through BLAST. The human TMEM19 protein is closely related to vertebrates and moderately related to fungi/plants. TMEM19 evolves at a rate that is related to cytochrome c.

Orthologs of Human TMEM19!Common Name!Class!Order!Genus and Species!Median Date of Divergence!Accession Number!Sequence Length!Sequence Identity to Humans %!Sequence Similarity to Humans %

Humans	Mammal	Primates	Homo sapiens	0	NP_060749.2^[17]	336	100	100
Mouse	Mammal	Rodentia	Mus musculus	87	NP_001346399.1^[18]	351	87.46	90.3
Meerkat	Mammal	Carnivora	Suricata suricatta	94	XP_029810978.1^[19]	336	91.92	96.4
Jamaican Fruit Bat	Mammal	Bats	Artibeus jamaicensis	94	XP_037017069.2^[20]	336	90.45	95.5
Baiji Dolphin	Mammal	Artiodactyla	Lipotes vexillifer	94	XP_007448836.1^[21]	358	89.58	90.8
Leatherback Turtle	Reptile	Testudines	Dermochelys coriacea	319	XP_038233118.1^[22]	335	82.26	89.9
Schlegal's Japanese Gecko	Reptile	Squamata	Gekko japonicus	319	XP_015261175.1^[23]	282	81.23	77.4
Burmese Python	Reptile	Squamata	Python bivittatus	319	XP_007423004.1^[24]	371	80.06	80.1
Viviparous Lizard	Reptile	Squamata	Zootoca vivipara	319	XP_034984278.1^[25]	336	79.85	88.3
Emu	Bird	Casuariiformes	Dromaius novaehollandiae	319	XP_025956153.1^[26]	336	77.38	89.3
Black Legged Kittiwake	Bird	Charadriiformes	Rissa tridactyla	319	XP_054044439.1^[27]	367	77.31	82.3
Japanese Quail	Bird	Galliformes	Coturnix japonica	319	XP_015711317.1^[28]	344	76.13	86.4
California Condor	Bird	Gymnogyps	Accipitriformes	319	XP_050753817.1^[29]	336	77.4	89.6
African Clawed Frog	Amphibian	Anura	Xenopus laevis	352	NP_001085034.1^[30]	336	76.12	89.3
Two-Lined Caecillian	Amphibian	Gymnophiona	Rhinatrema bivittatum	352	XP_029453037.1^[31]	336	76.12	89.3
Asian Arowana	Fish	Osteoglossiformes	Scleropages formosus	429	XP_018611167.1^[32]	336	69.33	84.5
Pacific Halibut	Fish	Pleuronectiformes	Hippoglossus stenolepis	429	XP_035003305.1^[33]	335	67.87	83
Sea Lamprey	Fish	Petromyzontiformes	Petromyzon marinus	563	XP_032815808.1^[34]	362	63.35	73
Zebra Shark	Fish	Orectolobiformes	Stegostoma tigrinum	462	XP_048404699.1^[35]	354	73.59	80.5
Pin Mould	Fungi	Mucorales	Mucor mucedo	1275	XP_051459555.1^[36]	284	32.8	47.7
Ascomycete Fungi	Fungi	Helotiales	Lachnellula hyalina	1275	XP_031007997.1^[37]	383	23.3	35.9
Thale Cress	Plant	Brassicales	Arabidopsis thaliana	1598	NP_001190343.1^[38]	288	34.6	50

Notes and References

1. Fu S, Liu J . Genome-wide association study identified genes associated with ammonia nitrogen tolerance in Litopenaeus vannamei . Frontiers in Genetics . 13 . 961009 . 2022-08-22 . 36072655 . 9441690 . 10.3389/fgene.2022.961009 . free .
2. Yu Y, Zuo X, He M, Gao J, Fu Y, Qin C, Meng L, Wang W, Song Y, Cheng Y, Zhou F, Chen G, Zheng X, Wang X, Liang B, Zhu Z, Fu X, Sheng Y, Hao J, Liu Z, Yan H, Mangold E, Ruczinski I, Liu J, Marazita ML, Ludwig KU, Beaty TH, Zhang X, Sun L, Bian Z . 6 . Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity . Nature Communications . 8 . 14364 . February 2017 . 28232668 . 5333091 . 10.1038/ncomms14364 . 2017NatCo...814364Y .
3. Yu X, Guo Z, Fang Z, Yang K, Liu C, Dong Z, Liu C . Identification and validation of disulfidptosis-associated molecular clusters in non-alcoholic fatty liver disease . Frontiers in Genetics . 14 . 1251999 . 2023-09-08 . 37745847 . 10514914 . 10.3389/fgene.2023.1251999 . free .
4. Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, Zhang J, Soden R, Hayakawa M, Kreiman G, Cooke MP, Walker JR, Hogenesch JB . 6 . A gene atlas of the mouse and human protein-encoding transcriptomes . Proceedings of the National Academy of Sciences of the United States of America . 101 . 16 . 6062–6067 . April 2004 . 15075390 . 395923 . 10.1073/pnas.0400782101 . free . 2004PNAS..101.6062S .
5. Web site: MC4R melanocortin 4 receptor [Homo sapiens (Human)] - Gene - NCBI .
6. Web site: BSCL2 BSCL2 lipid droplet biogenesis associated, seipin [Homo sapiens (Human)] - Gene - NCBI .
7. https://www.ncbi.nlm.nih.gov/gene/116519
8. Web site: AQP6 aquaporin 6 [Homo sapiens (Human)] - Gene - NCBI .
9. https://www.ncbi.nlm.nih.gov/gene/256815
10. Web site: CD3G CD3 gamma subunit of T-cell receptor complex [Homo sapiens (Human)] - Gene - NCBI .
11. Web site: CD79A CD79a molecule [Homo sapiens (Human)] - Gene - NCBI .
12. Web site: CNR2 cannabinoid receptor 2 [Homo sapiens (Human)] - Gene - NCBI .
13. Web site: CPLX4 complexin 4 [Homo sapiens (Human)] - Gene - NCBI .
14. Web site: CREB3 cAMP responsive element binding protein 3 [Homo sapiens (Human)] - Gene - NCBI .
15. Web site: CREB3L1 cAMP responsive element binding protein 3 like 1 [Homo sapiens (Human)] - Gene - NCBI .
16. Web site: The CUCKOO Workgroup . 2023-12-07 . biocuckoo.org.
17. Web site: Transmembrane protein 19 [Homo sapiens] - Protein - NCBI .
18. Web site: Transmembrane protein 19 isoform 1 [Mus musculus] - Protein - NCBI .
19. Web site: Transmembrane protein 19 [Suricata suricatta] - Protein - NCBI .
20. Web site: Transmembrane protein 19 [Artibeus jamaicensis] - Protein - NCBI .
21. Web site: PREDICTED: Transmembrane protein 19 [Lipotes vexillifer] - Protein - NCBI .
22. Web site: Transmembrane protein 19 isoform X1 [Dermochelys coriacea] - Protein - NCBI .
23. Web site: PREDICTED: Transmembrane protein 19, partial [Gekko japonicus] - Protein - NCBI .
24. Web site: Transmembrane protein 19 isoform X1 [Python bivittatus] - Protein - NCBI .
25. Web site: Transmembrane protein 19 isoform X2 [Zootoca vivipara] - Protein - NCBI .
26. Web site: Transmembrane protein 19 [Dromaius novaehollandiae] - Protein - NCBI .
27. Web site: Transmembrane protein 19 [Rissa tridactyla] - Protein - NCBI .
28. Web site: Transmembrane protein 19 [Coturnix japonica] - Protein - NCBI .
29. Web site: Transmembrane protein 19 [Gymnogyps californianus] - Protein - NCBI .
30. Web site: Transmembrane protein 19 [Xenopus laevis] - Protein - NCBI .
31. Web site: Transmembrane protein 19 [Rhinatrema bivittatum] - Protein - NCBI .
32. Web site: Transmembrane protein 19 [Scleropages formosus] - Protein - NCBI .
33. Web site: Transmembrane protein 19 [Hippoglossus stenolepis] - Protein - NCBI .
34. Web site: Transmembrane protein 19 isoform X1 [Petromyzon marinus] - Protein - NCBI .
35. Web site: Transmembrane protein 19 isoform X1 [Stegostoma tigrinum] - Protein - NCBI .
36. Web site: Integral membrane protein DUF92-domain-containing protein [Mucor muced - Protein - NCBI .
37. Web site: Transmembrane protein [Lachnellula hyalina] - Protein - NCBI .
38. Web site: Integral membrane protein (Protein of unknown function DUF92, transmem - Protein - NCBI .