Shisa-8
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Shisa-8 is a protein that is humans is encoded by C22orf17 (Chromosome 22 Open Reading Frame 17) gene. 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.{{cite web | title = SHISA8 shisa family member 8 [ Homo sapiens (human) ] | url = https://www.ncbi.nlm.nih.gov/gene/440829 | website = NCBI | publisher = NIH | access-date = 3 December 2024 }} AMPA receptors are predicted to have effects on learning, memory, and gating properties in neurons.{{cite journal | vauthors = Liu S, Wang J, Tian X, Zhang Z, Wang L, Xiong Y, Liu X, Xie Y, Wu X, Xu C | title = An integrated multi-omics analysis identifies novel regulators of circadian rhythm and sleep disruptions induced by changed photoperiod in Antarctica | journal = Molecular Psychiatry | date = 2024 | pmid = 39587296 | doi = 10.1038/s41380-024-02844-7 | url = https://pubmed.ncbi.nlm.nih.gov/39587296/ | publisher = NIH | access-date = 3 December 2024 | doi-access = free }}{{cite journal | vauthors = Nejat M, Klaassen RV, Spijker S, Smit AB | title = Auxiliary subunits of the AMPA receptor: The Shisa family of proteins | journal = Current Opinion in Pharmacology | volume = 58 | pages = 52–61 | date = 2021 | pmid = 33892364 | doi = 10.1016/j.coph.2021.03.001 | url = https://pubmed.ncbi.nlm.nih.gov/33892364/ | publisher = NIH | hdl = 1871.1/e9e9a0c2-d7ca-4ebf-a2af-4d09624c4d4f | access-date = 3 December 2024 | hdl-access = free }}
Gene
=Aliases=
the protein Shisa-8 only has one distinct alias, C22orf17.{{cite web | title = SHISA8 Gene - Shisa Family Member 8 | url = https://www.genecards.org/cgi-bin/carddisp.pl?gene=SHISA8&keywords=shisa8 | website = GeneCard | access-date = 3 December 2024 }}
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.{{cite web | title = SHISA8 Gene - Shisa Family Member 8 | url = https://www.genecards.org/cgi-bin/carddisp.pl?gene=SHISA8&keywords=shisa8 | website = GeneCard | access-date = 3 December 2024 }}
=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.{{cite web | title = SHISA8 shisa family member 8 [ Homo sapiens (human) ] | url = https://www.ncbi.nlm.nih.gov/gene/440829 | website = NCBI | publisher = NIH | access-date = 3 December 2024 }}{{cite web | title = Chapter 10 Synthesis and Processing of RNA | url = https://www.ncbi.nlm.nih.gov/books/NBK21132/ | website = NCBI | publisher = NIH | access-date = 13 December 2024 }}
=Transcript variants=
= Protein =
=Structure=
Shisa-8 is a membrane bound protein associated with AMPA receptors that has 4 isoforms{{cite web | title = SHISA8 shisa family member 8 [ Homo sapiens (human) ] | url = https://www.ncbi.nlm.nih.gov/gene/440829 | website = NCBI | publisher = NIH | access-date = 3 December 2024 }} and is a class of transporters only found in the plasma membrane currently.{{cite web | title = Shisa-8 | url = https://www.proteinatlas.org/ENSG00000234965-SHISA8 | website = Human Protein Atlas | access-date = 3 December 2024 }} 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.{{cite journal | vauthors = Engelhardt J | title = AMPA Receptor Auxiliary Proteins of the CKAMP Family | journal = International Journal of Molecular Sciences | volume = 20 | issue = 6 | pages = 1460 | date = 2019 | pmid = 30909450 | pmc = 6470934 | doi = 10.3390/ijms20061460 | publisher = NIH | doi-access = free }} Shisa-8 contains a Pfam1308 domain and acts as an antagonist to Wnt and FGF signaling critical for brain development or neurotransmitter. regulation.{{cite journal | vauthors = Maino B, Ciotti MT, Calissano P, Cavallaro S | title = Transcriptional analysis of apoptotic cerebellar granule neurons following rescue by gastric inhibitory polypeptide | journal = International Journal of Molecular Sciences | volume = 15 | issue = 4 | pages = 5596–5622 | date = 2014 | pmid = 24694544 | pmc = 4013584 | doi = 10.3390/ijms15045596 | publisher = NIH | doi-access = free }}{{cite journal | vauthors = Rao CV, Farooqui M, Zhang Y, Asch AS, Yamada HY | title = Spontaneous development of Alzheimer's disease-associated brain pathology in a Shugoshin-1 mouse cohesinopathy model | journal = Aging Cell | volume = 17 | issue = 4 | pages = e12797 | date = 2018 | pmid = 29943428 | pmc = 6052391 | doi = 10.1111/acel.12797 | publisher = NIH }}
=Isoform characteristics=
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| 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 |
File:Shisa-8 N-terminus Structure by I-tasser.pngTertiary Structure
File:Annotated tertiary structure of Shisa-8.png
File:Shisa-8 C-Terminus Structure Created by I-tasser.png
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.{{cite web | title = I-Tasser | url = https://zhanggroup.org/I-TASSER/ | website = I-Tasser | access-date = 3 December 2024 }}{{cite web | title = Protein shisa-8 | url = https://alphafold.ebi.ac.uk/entry/B8ZZ34 | website = AlphaFold | publisher = EMBL-EBI | access-date = 13 December 2024 }} 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.{{cite journal | vauthors = Kay BK, Williamson MP, Sudol M | title = The Importance of being Proline: the Interaction of Proline Rich Motifs in Signaling Proteins with their Cognate Domain | journal = FASEB Journal | volume = 14 | issue = 2 | pages = 231–241 | date = 2000 | pmid = 10657980 | doi = 10.1096/fasebj.14.2.231 | doi-access = free }}
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.{{cite web | title = Microarray assessed tissue expression patterns of C22orf17 from NCBI GEO GDS4794 | url = https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS4794:244467_at | website = NCBI | publisher = NIH | access-date = 3 December 2024 }} 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.{{cite web | title = Shisa-8 Protein Abundance | url = https://pax-db.org/protein/9606/ENSP00000481203 | website = PaxDB | access-date = 3 December 2024 }}
=Protein level regulation=
Shisa-8 was found to be localized to the plasma membrane of a cell.{{cite web | title = DeepLoc DTU | url = https://services.healthtech.dtu.dk/services/DeepLoc-2.0/ | website = DTU Health Tech | access-date = 3 December 2024 }} "It was also found to have a signal peptide from AA38 to AA39 translocating the protein to the plasma membrane.{{cite web | title = TargetP DTU | url = https://services.healthtech.dtu.dk/services/TargetP-2.0/ | website = DTU Health Tech | access-date = 3 December 2024 }}{{cite web | title = SignalP DTU | url = https://services.healthtech.dtu.dk/services/SignalP-5.0/ | website = DTU Health Tech | access-date = 3 December 2024 }} Shisa-8 has several post-translantional modifications including N-linked glycosylation, O-glycosylation, Phosphorylation, and SUMOylation.{{cite web | title = DTU Health Tech | url = https://services.healthtech.dtu.dk/ | website = DTU Health Tech | access-date = 3 December 2024 }}
Evolution
Paralogs
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| 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 |
File:Shisa-8 Phylogenetic Tree.png
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.{{cite journal | vauthors = Nejat M, Klaassen RV, Spijker S, Smit AB | title = Auxiliary subunits of the AMPA receptor: The Shisa family of proteins | journal = Current Opinion in Pharmacology | volume = 58 | pages = 52–61 | date = 2021 | pmid = 33892364 | doi = 10.1016/j.coph.2021.03.001 | url = https://www.sciencedirect.com/science/article/pii/S1471489221000217 | publisher = Elseveir | hdl = 1871.1/e9e9a0c2-d7ca-4ebf-a2af-4d09624c4d4f | access-date = 13 December 2024 | hdl-access = free }}
=Orthologs=
File:Shisa-8 Ortholog Table(corrected).png
Shisa-8 orthologs were found in vertebrates and cartilaginous fish.{{cite web | title = NCBI BLAST | url = https://blast.ncbi.nlm.nih.gov/Blast.cgi | website = NCBI | publisher = NIH | access-date = 3 December 2024 }} 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.{{cite journal | vauthors = Pei J, Grishin NV | title = Unexpected diversity in Shisa-like proteins suggests the importance of their roles as transmembrane adaptors | journal = Cellular Signalling | volume = 24 | issue = 3 | pages = 758–769 | date = 2011 | pmid = 22120523 | pmc = 3295595 | doi = 10.1016/j.cellsig.2011.11.011 | publisher = NIH }} 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{{cite web | title = NCBI BLAST | url = https://blast.ncbi.nlm.nih.gov/Blast.cgi | website = NCBI | publisher = NIH | access-date = 3 December 2024 }}
=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
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| 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.{{cite journal | vauthors = Hentges KE, Yarlagadda SP, Justice MJ | title = Tnfrsf13c (Baffr) is Mis-expressed in Tumors with Murine Leukemia Virus Insertions at Lvis22 | journal = Genomics | volume = 80 | issue = 2 | pages = 204–212 | date = 2002 | pmid = 12160734 | doi = 10.1006/geno.2002.6812 | url = https://www.sciencedirect.com/science/article/pii/S0888754302968126?ref=pdf_download&fr=RR-2&rr=8f18af3f8e26dadb | publisher = Elseveir | access-date = 13 December 2024 }}
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.{{cite web | title = Microarray assessed tissue expression patterns of C22orf17 from NCBI GEO GDS4794 | url = https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS4794:244467_at | website = NCBI | publisher = NIH | access-date = 3 December 2024 }}
References
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