# TMEM61

Transmembrane protein 61 (TMEM61) is a protein that is encoded by the TMEM61 gene in humans. It is located on the first chromosome in humans and is highly expressed in the intestinal regions predominantly the kidney, adrenal gland and pituitary tissues. The protein, unlike other transmembrane protein in the region does not promote cancer growth. However, the TMEM61 protein when inhibited by secondary factors restricts normal activity in the kidney. The human protein shares many Orthologs and has been prevalent on Earth for millions of years.

## Gene
### Aliases

There are no known aliases of TMEM61. The human protein can be identified with any tool that uses UniProt by Q8N0U2.

### Location

TMEM61 is located on the plus strand of the human chromosome 1 at the locus 1 p32.3. The gene is 11, 661 base pairs long, it ranges from position 54,980,628 to 54,992,288 on chromosome 1. TMEM61 lies between LOC124904184 and BSND.

### Transcript variants

NCBI RefSeq contains seven mRNA transcript variants for TMEM61. Transcription variants X1, X2, and X2 both are splices of the original protein, but all three isoforms have their own variants. None of the variants share similar exon boundaries, domain or disordered regions.
| Name | Accession Number | Number of Exons | Domain | Size (bp) |
| Transcript Variant 1 | NM_182532.3 | 3 | 2 | 1256 |
| Transcript Variant X1 | XM_011540911.3 | 0 | 0 | 971 |
| Transcript Variant X2 | XM_005270586.5 | 0 | 0 | 844 |
| Transcript Variant X2 | XM_011540912.3 | 0 | 0 | 1747 |
| Transcript Variant X1 | XM_054334900.1 | 0 | 0 | 998 |
| Transcript Variant X2 | XM_054334901.1 | 0 | 0 | 865 |
| Transcript Variant X2 | XM_054334902.1 | 0 | 0 | 1747 |

## Protein
### Isoforms

There are six known Isoforms of the TMEM61 protein, Isoform X1 is encoded by transcript variant X1, and Isoform X2 with variant X2 and so on. There are two different X2 isoforms, but both have the same amino acid sequence, both the X2 have five less amino acids in the start of the protein, which differs from isoform X1 with same protein sequence and size as the original protein.
| Name | Accession Number | Size (aa) | Predicted Molecular Weight (kDa) |
| Isoform 1 | NP_872338.1 | 210 | 22.2 |
| Isoform X1 | XP_011539213.1 | 210 | 22.2 |
| Isoform X2 | XP_005270643.1 | 205 | 21.6 |
| Isoform X2 | XP_011539214.1 | 205 | 21.6 |
| Isoform X1 | XP_054190875.1 | 210 | 22.2 |
| Isoform X2 | XP_054190876.1 | 205 | 21.6 |
| Isoform X2 | XP_054190877.1 | 205 | 21.6 |

### Protein characteristics

The Isoform 1 of the TMEM61 protein is made up of 210 amino acids. The protein has a predicted molecular weight of about 22.2 KDa and a theoretical isoelectric point of about 4.54. In terms of amino acid composition, TMEM61 is relatively rich in both the hydrophobic Proline and hydrophilic Serine. The protein is relatively poor in both hydrophilic Asparagine and Lysine. It is also poor in both hydrophobic Isoleucine and Phenylalanine. The protein indicates acid components from it addition of Arginine and Lysine subtracted to the addition of Glutamic Acid and Aspartic Acid.

### Domains

TMEM61 Isoform 1 contains two transmembrane domains one of encompasses a DUF domain. TMEM61 also contains a MTP domain, unlike the transmembrane domain this domains located in the Golgi Apparatus and involves spanning transportation. All four domain regions had low value scores except the second TMEM domain was not able to be scored.
| Domain Name | Amino Acid |
| TMEM | 18-38 |
| DUF308 | 16-37 or 16-41 |
| TMEM | 69-89 |
| MTP | 124-152 |

### Secondary structure

The Ali2D, and I-TASSER models predicted that the secondary structure of TMEM61 has both alpha helices and beta strands.

### Tertiary structure

No confident model for tertiary structure for TMEM61.

### Post-translational modifications

While the modification are few, phosphorylation will not result in a change oil the amino acid for TMEM61, this is a result of the lack of glycosylation that takes place in the sequence. Results are represented by graph on bottom right.
| TMEM61 Sites | Kinase | Tools |
| V26-30 | N/A | GPS-Sumo |
| K90 | N/A | GPS-Sumo |
| S10 | AGC | GPS |
| S14 | AGC | GPS |
| T15 | AGC | GPS |
| T21 | AGC | GPS |
| T23 | AGC | GPS |
| T25 | AGC | GPS |
| T32 | AGC | GPS |
| S39 | AGC | GPS |
| T44 | AGC | GPS |
| T54 | AGC | GPS |

### Subcellular localization

Immunofluorescent standing experiments have detected the TMEM61 protein in the endocrine tissues, kidney and Urinary bladder, and proximal digestive tract. The experiment also found slight expression in the brain tissues.

## Regulation and expression
### Transcription factors

| Position | Score | strand | TranscriptionFactor Name |
| 473 | 682 | + | E2F6\ |
| 376 | 528 | - | TFAP2B\ |
| 58 | 514 | - | KLF4\ |
| 170 | 522 | - | NFIC\ |
| 564 | 548 | + | Tbx6\ |
| 488 | 537 | + | PLAG1\ |
| 235 | 512 | - | THAP1\ |
| 376 | 510 | + | TFAP2C\ |
| 59 | 494 | + | KLF10\ |
| 376 | 493 | - | TFAP2A\ |
| 53 | 489 | - | ZNF707\ |
| 60 | 469 | + | ZNF816\ |
| 376 | 465 | + | TFAP2B\ |
| 477 | 463 | - | ZNF460\ |
| 132 | 471 | + | Prdm5\ |
| 201 | 469 | + | TWIST1\ |
| 59 | 446 | + | KLF14\ |
| 203 | 419 | - | HAND2\ |
| 308 | 472 | + | PBX1\ |

### Tissue specificity

According to HumanAtlas, Geoprofile, and NCBI, TMEM61 is highly expressed in the Kidney, Pituitary gland, Salivary gland, Adrenal, and brain tissues in a decreasing order.

### Embryonic development

In situ hybridization staining a mouse embryo discovered high levels of TMEM61 in Kidneys and found no other tissues to express the protein.

### Immunochemistry

TMEM61 was found to be very abundant in the human body in comparison to other proteins.
Western blotting showed an over expression of lysate in mammalian, in this case rabbit.
The staining of the human pancreas shows cytoplasmic positivity in exocrine cells.

## Interacting proteins

The IntAct, String, and BioGrid database found eight relevant interacting protein to the TMEM61. Other TMEM protein such as TMEM124 are closely monitored together for the cancer expression both in the same region but both did not promote cancer growth.
| Interacting Protein | Interaction | Database | Publication notes |
| YAP1 | K on 118 of the sequence In vitro direct interaction | BioGrID InTACT | Protein-peptide |
| HSPA2 | Positive interaction via two hybrid array, pooling | INTACT | 32814053 10.1016/j.celrep.2020.108050 |
| TMEM45B | TMEM61 domain 2 region binding | String | PMID 34638224 |
| FGFR3 | Two hybrid array pooling, with physical association | INTACT | Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains |
| SARS1 | Host organism: Saccharomyces cerevisiae (Baker's yeast), Neurodegeneration testing affiliation | INTACT | Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains$^{[1]}$ |
| TMEM213 | Interacts with TMEM61 second domain | String | PMID 34638224 |

## Homology and evolution
### Orthologs and paralogs

TMEM61 has orthologs in mammals, reptiles, aves, amphibians, and fish. A table of orthologs is beside to the right. There is no known paralog of TMEM61.

### Evolutionary history

West African lungfish is the furthest-from-human known organism to express TMEM61 approximately 408 million years ago. The expression of TMEM61 protein throughout its closely related orthologs all indicate high expression in the Kidney.Based on a molecular clock analysis, the protein sequence of TMEM61 has on average evolved faster than Cytochrome C but slower than Fibrinogen alpha.

## Clinical significance

TMEM61 was anticipated to be associated with the formation of brain tumors but was later debunked as there was low levels expressed, however the test did indicate its location to be in the mitochondrial neural membrane region. The TMEM61 has been hoped to promote cancer or tumor growth but there has been no clinical research that proves this idea.
The information obtained about the TMEM61 does show expression on the kidney beyond it human organism and the studies show MIF limiting the expression of TMEM61.
The Aquaporin-11 deficiency, closing or breaking of water channels limits the protein expression in the membrane and restricts TMEM61 expression and inhibits kidney function.

### Interacting proteins

Very close to other TMEM protein such as TMEM124 was closely monitored for the cancer expression both in the same region but both did not promote cancer growth. PMP22, YAP1.