# Shisa-8

Shisa-8 is a protein encoded by the Human gene C22orf17 (Chromosome 22, Open Reading Frame 17). The longest isoform of the Shisa-8 mRNA is Isoform 1 spanning 5,532 nucleotides (nt). The Shisa-8 protein has been associated with alpha-amino-3-hydroxy-5-methyl-4-isooxazole-propionic acid (AMPA) receptors and is part of the AMPA receptor complex. AMPA receptors are predicted to have effects on learning, memory, and gating properties in neurons.

## Gene
### Aliases

the protein Shisa-8 only has one distinct alias, C22orf17.
Locus
The C22orf17 gene is located on the negative strand of Chromosome 22 (22q13.2) spanning 5,532 nt. It is found between two genes being MIR33A and TNFRSF13C.

### Exons

C22orf17 gene has a total of 4 exons and 3 introns. All of the introns are gt-ag, which is a very common structure that has been associated with RNA-binding regions that are involved in splicing.

### Transcript variants

C22orf17 has 4 isoforms: 1, 2, 3, and X1. Exons 1, 2, and 4 are identical in each isoform, with all differences in isoforms contained within exon 3. Isoform 1, 2, 3, and X1 coding sequences span 1,479, 1,371, 1,194, and 1,359 nt respectively, with Isoform 1 being the longest transcript.

### Structure

Shisa-8 is a membrane bound protein associated with AMPA receptors that has 4 isoformsand is a class of transporters only found in the plasma membrane currently. The protein consists of several regions including a N-terminus cysteine rich extracellular domain from AA1 to AA138 (Amino Acid), a transmembrane region from AA139 to AA159, C-terminus region with a proline rich region from AA186 to AA448 and a PDZ II domain. This cysteine rich region is highly conserved, showing its importance in interacting with AMPA receptors. The PDZ region allows the Shisa-8 protein to interact with other PDZ containing proteins. Shisa-8 contains a Pfam1308 domain and acts as an antagonist to Wnt and FGF signaling critical for brain development or neurotransmitter. regulation.

### Isoform characteristics

Caption text :
| Isoform Protein # | Accession # | mRNA length (nt) | Protein Length (aa) | Molecular Weight (kDa) | Variation in Exon 3 (nt) | Isoelectric point |
| 1 | NP_001340367 | 2108 | 492 | 51.0 | 431 | 10.8 |
| 2 | NP_001340368 | 2000 | 456 | 47.8 | 323 | 10.7 |
| 3 | NP_001193949 | 1823 | 397 | 41.9 | 146 | 10.6 |
| X1 | XP_006724319 | 1988 | 452 | 47.4 | No information | 10.7 |
Tertiary Structure
Tertiary Structure of the Shisa-8 Protein was created using I-tasser by breaking up the protein at the transmembrane region. Thus the extracellular N-terminus of Shisa-8 spans from AA1 to AA139 and the intracellular C-terminus spans from AA160 to AA462. Cleavage site for a signal peptide that spans from AA38-AA39 and is include on the Alphafold diagram.The N-terminus of Shisa-8 features a N-glycosylation site at AA75. In the C-terminus of Shisa-8, there is a proline rich region that is important for protein binding, especially SH3 protein binding domains that are associated with signal transduction.

## Expression
### Gene level regulation

Shisa-8 has the highest expression in the brain or with glands associated with the brain, specifically the cerebellum and adrenal gland. Shisa-8 was found to be ubiquitously expressed in all tissues tested, although expression in general was low, except in the brain and adrenal gland where expression was high. Protein abundance for Shisa-8 was on the lower end of abundance compared to other proteins. This finding was also shared by orthologs Water Buffalo and House Mouse.

### Protein level regulation

Shisa-8 was found to be localized to the plasma membrane of a cell. "It was also found to have a signal peptide from AA38 to AA39 translocating the protein to the plasma membrane. Shisa-8 has several post-translantional modifications including N-linked glycosylation, O-glycosylation, Phosphorylation, and SUMOylation.

## Evolution

Paralogs
Caption text :
| Protein Name | Accession # | Sequence Length (aa) | Sequence Identity (%) | Sequence Similarity (%) | E Value |
| Shisa-8 | NP_001340367 | 492 | 100 | 100 | 0 |
| Shisa-7 | NP_001138648.1 | 538 | 28.6 | 35.9 | 2E-25 |
| Shisa-6 | NP_001166932.1 | 551 | 22.8 | 33.0 | 8E-32 |
| Shisa-2 | NP_001007539.1 | 295 | 18.8 | 25.6 | 2E-5 |
| Shisa-9 | KAI2577232.1 | 221 | 17.7 | 22.2 | 2E-49 |
| Shisa-5 | NP_057563.3 | 240 | 15.7 | 20.5 | 3E-5 |
| Shisa-3 | NP_001073974.1 | 238 | 11.8 | 17.1 | 9E-5 |
| Shisa-4 | AAH61908.1 | 197 | 10.6 | 15.7 | 2E-5 |
Shisa-8 is a part of the Shisa family of proteins with Shisa-6 and Shisa-7 being found to be the most similar paralogs. Shisa 9, 7, and 6 were also shown to have a role in allosteric modulation of AMPA receptors.

### Orthologs

Shisa-8 orthologs were found in vertebrates and cartilaginous fish. Theories of Shisa-8 origins conclude that it either resulted from a gene duplication from Shisa-9, or was present in the last common ancestor of vertebrates. Of all vertebrates, the most divergent ortholog found was a Petromyzon marinus (Sea Lamprey). Shisa-8 diverged from Petromyzon marinus approximately 462 million years ago

### Rate of evolution

Using Cytochrome C and Fibrinogen Alpha divergence rates, Shisa-8 divergence rates were moderate compared to Fibrinogen Alpha and Cytochrome C divergence rates. This seems to indicate that Shisa-8's rate of mutation rate is moderate.

## Interacting proteins

Caption text :
| Abbreviated Name | Full Name | Score | Function |
| SHISA9 | SHISA9 | 0.728 | - Promotes AMPA receptor desensitization -Regulator of short-term neuronal plasticity |
| GRIN1 | Glutamate receptor ionotropic, NMDA 1 | 0.612 | -Heterotetrameric ligand-gated ions channels with high calcium permeability and magnesium sensitivity |
| SHISA7 | SHISA7 | 0.604 | -May affect AMPAR channel kinetics -Regulates GABA(A)R trafficking, channel deactivation kinetics and pharmacology |
| CNIH2 | Protein cornichon homolog 2 | 0.588 | -Regulates the trafficking and gating of AMPARs -Blocks CACNG8-mediated resensitization of AMPA receptors |
| OLFM2 | Noelin-2 | 0.581 | -involved in TGF-β induced smooth muscle differentiation -Role in AMPAR complex organization |
| LDLRAD1 | Low density lipoprotein receptor class A domain containing 1 | 0.580 | None |
| GRIN2C | Glutamate receptor ionotropic, NMDA 2C | 0.578 | -Heterotetrameric ligand-gated ions channels with high calcium permeability and magnesium sensitivity |
| CACNG3 | Voltage-dependent calcium channel gamma-3 subunit | 0.572 | -Regulates the trafficking to the somatodendritic compartment and gating properties of AMPARs |
| PTK2B | Protein-tyrosine kinase 2-beta | 0.569 | -regulate the reorganization of actin cytoskeleton -regulation of humoral immune response |
| GRIA2 | Glutamate receptor 2 | 0.566 | -ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission |

## Clinical significance

The c22orf17 gene has been associated with brain tumors, colon tumors, and lymphoma cancers due to expression of EST clones of similar sequence being shown.
Shisa-8 has been shown to be repressed in patients experiencing Chronic B-lymphocyte Leukemia (Chronic Lymphocytic Leukemia) and breast cancer with alpha-silenced MC7 estrogen receptors. In endothelial tissues, Shisa-8 was also found to be expressed in a great amount in Schizophrenic patient's tissue compared to healthy tissue.