SBK3

SBK3 is found on the minus strand of chromosome 19 in humans: 19q13.42.{{cite web |title=SBK3 Gene |url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=SBK3 |website=Gene Cards |access-date=27 April 2020}} Its reference isoform consists of 4,985 bases. Nearby genes include SBK2, a paralog to SBK3, as well as SSC5D, ZNF579, and FIZ1.{{cite web |title=SBK3 |url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=100130827 |website=NCBI Gene |publisher=NCBI}}

SBK3 has five exons; however, only four are included in the final mRNA transcript.{{cite web |title=SBK3 Gene |url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=SBK3 |website=Gene Cards}} SBK3 is found to have one isoform outside of its typical transcript. The reference isoform does not include exon 2 and isoform X1 does not include exon 1.{{cite web |title=SBK3 |url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=100130827 |website=NCBI Gene |publisher=NCBI}}

SBK3's reference protein has a predicted molecular mass of 38.5 kDa and an isoelectric point of 4.71 pI.{{cite web |title=Compute pI/Mw |url=https://web.expasy.org/compute_pi/ |website=ExPASy}} SBK3 has a significantly higher presence of proline amino acids than most proteins, which aligns with its proline-rich compositional bias that spans residues 189-278.{{cite web |title=SAPS |url=https://www.ebi.ac.uk/Tools/seqstats/saps/ |website=EMBL-EBI}} The exact function of this proline-rich region in SBK3 is yet to be determined; however, prior research states that it's the region in which the SH3 domain of interacting proteins binds to SBK3.{{cite book | vauthors = Pollard T, Earnshaw W, Lippincott-Schwartz J, Johnson G |title=Cell Biology |date=30 November 2016 |publisher=Elsevier |edition=3rd}}

As previously stated, SBK3's reference protein is made up of 359 amino acids. The polypeptide chain that results from the translation of SBK3 into the SBK3 protein is shown below. A non-canonical polyadenylation signal ‘TATAAA’ is found 622 bases downstream from the stop codon.{{cite journal | vauthors = Kalkatawi M, Rangkuti F, Schramm M, Jankovic BR, Kamau A, Chowdhary R, Archer JA, Bajic VB | display-authors = 6 | title = Dragon PolyA Spotter: predictor of poly(A) motifs within human genomic DNA sequences | journal = Bioinformatics | volume = 29 | issue = 11 | pages = 1484 | date = June 2013 | pmid = 23616439 | doi = 10.1093/bioinformatics/btt161 | doi-access = free }}

File:Conceptual SBK3 Translation.png

SBK3 has a large conserved catalytic domain specific to the protein kinase superfamily.{{cite web |title=SBK3 |url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=100130827 |website=NCBI Gene |publisher=NCBI}} Nineteen ATP-binding sites found in SBK3’s paralog, SBK1, are all conserved in SBK3. The tyrosine motif exists in SBK3 (residues 44-233) and is found to overlap the conserved protein kinase superfamily domain (residues 49-208).{{cite web |title=MOTIF Search |url=https://www.genome.jp/tools/motif/ |website=MOTIF Search}} SBK3's active site (ACT) is predicted to span residues 159-171.{{cite web |title=Motif Scan |url=https://myhits.isb-sib.ch/cgi-bin/motif_scan |website=Motif Scan |publisher=ExPASy}} A cross-program analysis revealed a predicted transmembrane domain (TMD) approximately spanning residues 224-240.{{cite web |title=Phobius |url=http://phobius.sbc.su.se/ |website=Phobius}}{{cite web |title=Prediction of Transmembrane Regions and Orientation |url=https://embnet.vital-it.ch/software/TMPRED_form.html |website=TMpred |publisher=ExPASy |access-date=2020-05-03 |archive-date=2019-03-05 |archive-url=https://web.archive.org/web/20190305234532/https://embnet.vital-it.ch/software/TMPRED_form.html |url-status=dead }}{{cite web |title=Phyre2 |url=http://www.sbg.bio.ic.ac.uk/~phyre2/html/page.cgi?id=index |website=Phyre2}}{{cite web |title=PSIPRED |url=http://bioinf.cs.ucl.ac.uk/psipred/ |website=PSIPRED |publisher=UCL Department of Computer Science: Bioinformatics Group}}{{cite web |title=Protein Subcellular Localization Prediction Tool |url=https://www.genscript.com/psort.html?src=leftbar |website=PSORT |publisher=GenScript}}{{cite web | vauthors = Mitaku S, Hirokawa T |title=SOSUI |url=http://harrier.nagahama-i-bio.ac.jp/sosui/sosui_submit.html |website=SOSUI}}{{cite web | vauthors = Jones D |title=SACS MEMSAT2 Transmembrane Prediction Page |url=http://www.sacs.ucsf.edu/cgi-bin/memsat.py |website=SACS MEMSTAT2}} A SUMO-interacting motif (SIM) is predicted to span residues 298-302.{{cite web |title=Prediction of SUMOylation Sites & SUMO-binding Motifs |url=http://www.sumosp.biocuckoo.org/ |website=GPS-SUMO |publisher=GPS}}

{{multiple image

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| image1 = SBK3 Annotation of Domains and PTMs.png

| alt1 = Domains

| caption1 = Illustration of SBK3's predicted domains, motifs, and post-translational modifications.

| image2 = SBK3's Predicted Transmembrane Domain.png

| alt2 = TMD

| caption2 = Visual depiction of SBK3's predicted transmembrane domain created through Protter.{{cite web |title=Protter |url=http://wlab.ethz.ch/protter/ |website=Protter}}

}}

File:Secondary Structure SBK3.png

A cross-program analysis predicted SBK3's secondary structure to consist of eight alpha helices and two beta sheets.{{cite web |title=Phyre2 |url=http://www.sbg.bio.ic.ac.uk/~phyre2/html/page.cgi?id=index |website=Phyre2}}{{cite web |title=Prabi |url=https://npsa-prabi.ibcp.fr/cgi-bin/npsa_automat.pl?page=/NPSA/npsa_seccons.html |website=Prabi}}{{cite web |title=Chou and Fasman Secondary Structure Prediction server| vauthors = Ashok K |url=http://www.biogem.org/tool/chou-fasman/ |website=CFSSP}}{{cite web |title=Jpred4 |url=http://www.compbio.dundee.ac.uk/jpred/ |website=Jpred4}}{{cite web |title=Ali2D |url=https://toolkit.tuebingen.mpg.de/tools/ali2d |website=MPI Bioinformatics Toolkit}}

File:SBK3 3D Model.png.| 275 px|left]]

SBK3's predicted tertiary structure is shown to have many alpha-helices and few beta-sheets, thereby aligning with previous secondary structure predictions.{{cite web |title=I-TASSER |url=https://zhanglab.ccmb.med.umich.edu/I-TASSER/ |website=I-TASSER |publisher=Zhang Lab |access-date=21 April 2020}} Homologous proteins were analyzed to identify structural similarities. According to PHYRE2, SBK3's sequence is similar to that of the F chain of the α subunit of IκB kinase (73% query cover, 24% identical) which is involved in the upstream NF-κB signal transduction cascade.{{cite web |title=Phyre2 |url=http://www.sbg.bio.ic.ac.uk/~phyre2/html/page.cgi?id=index |website=Phyre2}} According to SWISS-MODEL, SBK3's sequence is 30% similar to mitogen-activated protein kinase 8 (MAPK8).{{cite web |title=SWISS-MODEL |url=https://swissmodel.expasy.org/ |website=SWISS-MODEL |publisher=ExPASy}}

The 1JC ligand is predicted to interact with the SBK3 protein (97% confidence).{{cite web |title=I-TASSER |url=https://zhanglab.ccmb.med.umich.edu/I-TASSER/ |website=I-TASSER |publisher=Zhang Lab |access-date=21 April 2020}} This ligand is functionally annotated to bind to a receptor tyrosine kinase called the hepatocyte growth factor receptor.{{cite web |title=BioLip |url=https://zhanglab.ccmb.med.umich.edu/BioLiP/getaid.cgi?id=0264121 |website=Ligand-Protein Binding Database |publisher=Zhang Lab}}

The location of SBK3's promoter and associated enhancer align with the concept of enhancer initiated transcription because their sequences, as found on chromosome 19, overlap. Recent studies have shown that enhancers can sometimes initiate transcription; however, the functional role of transcription initiation by enhancers is not yet defined.{{cite journal | vauthors = Tippens ND, Vihervaara A, Lis JT | title = Enhancer transcription: what, where, when, and why? | journal = Genes & Development | volume = 32 | issue = 1 | pages = 1–3 | date = January 2018 | pmid = 29440223 | pmc = 5828389 | doi = 10.1101/gad.311605.118 }}

Overall, SBK3 has low expression as it is expressed at only 4.6% of the average human gene.{{cite web |title=LOC100130827 |url=https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&term=SGK110&submit=Go |website=AceView |publisher=NCBI}} SBK3's highest levels of expression are in human cardiac muscle tissue, but it is also found to be expressed in skeletal muscle tissue.{{cite web |title=SBK3 |url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=100130827 |website=NCBI Gene |publisher=NCBI |access-date=27 April 2020}}{{cite web |title=Cell Atlas |url=https://www.proteinatlas.org/ENSG00000231274-SBK3/cell |website=The Human Protein Atlas}} During human fetal development, expression is the highest within the lung at 17 weeks.{{cite web |title=SBK3 |url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=100130827 |website=NCBI Gene |publisher=NCBI}} In mice, SBK3 is annotated as having biased expression primarily in adult heart tissue, which is followed by adult lung tissue.{{cite web |title=SBK3 |url=https://www.ncbi.nlm.nih.gov/gene/?term=sbk3+mus+musculus |website=NCBI Gene |publisher=NCBI}} However, in the mouse embryo, there is no evidence of biased expression.{{cite web |title=Gene Paint |url=https://gp3.mpg.de/results/SBK3 |website=Gene Paint}} In pig brains, the retina was shown to have the highest level of SBK3 expression.{{cite web |title=Cell Atlas |url=https://www.proteinatlas.org/ENSG00000231274-SBK3/cell |website=The Human Protein Atlas}}

A novel conditional nebulin knockout mouse model revealed an increase in SBK3 expression in the quadriceps and soleus muscles.{{cite journal | vauthors = Li F, Buck D, De Winter J, Kolb J, Meng H, Birch C, Slater R, Escobar YN, Smith JE, Yang L, Konhilas J, Lawlor MW, Ottenheijm C, Granzier HL | display-authors = 6 | title = Nebulin deficiency in adult muscle causes sarcomere defects and muscle-type-dependent changes in trophicity: novel insights in nemaline myopathy | journal = Human Molecular Genetics | volume = 24 | issue = 18 | pages = 5219–33 | date = September 2015 | pmid = 26123491 | pmc = 4550825 | doi = 10.1093/hmg/ddv243 }} The mice in this study were born with high nebulin levels in their skeletal muscle but nebulin expression rapidly fell within weeks after birth. This study observed that knockout mice that survived to adulthood experienced fiber-type switching towards oxidative types. Consequently, SBK3 expression was found to increase in the quadriceps and soleus muscles of nebulin conditional knockout mice.

In its 3'UTR, SBK3 is predicted to be targeted by four miRNAs: hsa-miR-637, hsa-miR-6077, hsa-miR-6760-5p, and hsa-miR-1291.{{cite web |title=miRDB |url=http://www.mirdb.org/ |website=miRDB}} All four miRNAs are conserved throughout primates and are identified to bind to stem-loop structures found within the 3' UTR.{{cite web |title=unafold |url=http://unafold.rna.albany.edu/?q=mfold/RNA-Folding-Form2.3 |website=unafold}}

File:SBK3 Post-Translational Modifications.png

SBK3 has 29 proposed phosphorylation sites at various serine, threonine, and tyrosine residues.{{cite web |title=NetPhos 3.1 Server |url=http://www.cbs.dtu.dk/services/NetPhos/ |website=NetPhos 3.1 Server |publisher=DTU Bioinformatics}} O-GlcNAc is predicted to occur at five threonines and one serine.{{cite web |title=YinOYang 1.2 Server |url=http://www.cbs.dtu.dk/services/YinOYang/ |website=YinOYang 1.2 Server |publisher=DTU Bioinformatics}} SUMOylation was predicted to occur at two lysine residues: K165 and K347; a SUMO-interacting motif was found between residues 298-302.{{cite web |title=Prediction of SUMOylation Sites & SUMO-binding Motifs |url=http://www.sumosp.biocuckoo.org/ |website=GPS-SUMO |publisher=GPS}} SBK3 is also predicted undergo C-mannosylation at a singular tryptophan residue: W258.{{cite web |title=NetCGlyc 1.0 Server |url=http://www.cbs.dtu.dk/services/NetCGlyc/ |website=NetCGlyc 1.0 Server |publisher=DTU Bioinformatics}}

Through the use of antibodies, SBK3 has been observed to localize to the mitochondria.{{cite web |title=Cell Atlas |url=https://www.proteinatlas.org/ENSG00000231274-SBK3/cell |website=The Human Protein Atlas}} PSORT's k-NN prediction determined that SBK3 was 39.1% likely to localize to the mitochondria and 21.7% likely to localize to the cytoplasm.{{cite web |title=PSORT II Prediction |url=https://psort.hgc.jp/form2.html |website=PSORT II Prediction}} The Reinhardt method predicted SBK3's localization to by cytoplasmic with a reliability score of 89.{{Cite web | url=https://psort.hgc.jp/form2.html |title = PSORT II Prediction}} No signal peptide has been found in SBK3.{{cite web |title=Phobius |url=http://phobius.sbc.su.se/ |website=Phobius}} Further analysis of SBK3's behavior in the cell is required to fully understand its subcellular localization.

As previously stated, SBK3 has two paralogs: SBK1 and SBK2.{{cite web |title=SBK3 |url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=100130827 |website=NCBI Gene |publisher=NCBI |access-date=27 April 2020}}

A total of 141 organisms are found to have orthologs with the SBK3 gene, all of which are jawed vertebrates. Of these 141 orthologs, 121 of them are mammals. SBK3 is not found in amphibians.{{cite web |title=SBK3 |url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=100130827 |website=NCBI Gene |publisher=NCBI |access-date=27 April 2020}}

SBK3 diverged from cartilaginous fishes around 400 years ago, birds and reptiles around 300 million years ago, non-primate mammals around 90 million years ago. Divergence from primates last occurred around nine million years ago.{{cite web |title=TimeTree |url=http://timetree.org/ |website=TimeTree}}

SBK3 is statistically predicted to be involved in sarcomere organization, regulation of muscle relaxation, cardiac myofibril assembly, and regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ions.{{cite web |title=SBK3 |url=https://maayanlab.cloud/archs4/gene/SBK3 |website=ARCHS4 |access-date=27 April 2020}} However, the function of SBK3 has yet to be well understood by the scientific community.

SBK3's promoter region was analyzed to identify predicted transcription factor binding sites (TFBS) that had high matrix similarity scores, close proximity to the transcription start site (TSS), high conservation throughout primates, and/or are a TATA-binding protein (TBP). Conserved matrix families of interest include KLFS and mammalian transcriptional repressor (RBPF) as they both pertain to cardiac differentiation and function.{{cite web |title=ElDorado |url=https://www.genomatix.de/cgi-bin/eldorado/eldorado.pl?s=6f526f56aebf2cdf499a13eb4041f5f9;RESULT=SBK3 |website=Genomatix |access-date=27 March 2020}}{{cite journal |author3-link=Ira Goldberg | vauthors = Pollak NM, Hoffman M, Goldberg IJ, Drosatos K | title = Krüppel-like factors: Crippling and un-crippling metabolic pathways | journal = JACC. Basic to Translational Science | volume = 3 | issue = 1 | pages = 132–156 | date = February 2018 | pmid = 29876529 | pmc = 5985828 | doi = 10.1016/j.jacbts.2017.09.001 | url = }}{{cite journal | vauthors = Desjardins CA, Naya FJ | title = Antagonistic regulation of cell-cycle and differentiation gene programs in neonatal cardiomyocytes by homologous MEF2 transcription factors | journal = The Journal of Biological Chemistry | volume = 292 | issue = 25 | pages = 10613–10629 | date = June 2017 | pmid = 28473466 | pmc = 5481567 | doi = 10.1074/jbc.M117.776153 | doi-access = free }}

File:Transcription Factor Binding Sites SBK3.png

According to STRING, SBK3 interacts with ADCK5, C3orf36, OR8B4, PRR32, RD3L, and SMCO1.{{cite web |title=Human SBK3 |url=https://version-12-0.string-db.org/cgi/network?networkId=bCSSsXm5ZlR9 |access-date=20 September 2023 |website=STRING |publisher=STRING CONSORTIUM 2023 |edition=Version 12.0}} According to Mentha, SBK3 interacts with SMAD3, MBD3L2, Q494R0, SNRNP35, A8MTQ0, AIMP2, DMAP1, EXOSC2, TNNT1, GATAD2B, and Q8WUT1.{{cite web |title=Mentha |url=https://mentha.uniroma2.it/ |website=Mentha}} SMAD3 is a receptor-regulated subtype of SMAD, which is shown to have a highly conserved TFBS in SBK3 with a high matrix similarity score.

{{multiple image

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| image1 = Mentha SBK3 Protein Interactions.png

| alt1 = Mentha

| caption1 = Mentha's predicted protein-protein interactions for SBK3 (P0C264).

| image2 = STRING 12.0 SBK3 Protein Interactions.png

| alt2 = STRING

| caption2 = STRING's predicted protein-protein interactions for SBK3.

}}

SBK3 has been shown to be enriched in hemostasis and signal transduction pathways.{{cite journal | vauthors = Wetherill L, Lai D, Johnson EC, Anokhin A, Bauer L, Bucholz KK, Dick DM, Hariri AR, Hesselbrock V, Kamarajan C, Kramer J, Kuperman S, Meyers JL, Nurnberger JI, Schuckit M, Scott DM, Taylor RE, Tischfield J, Porjesz B, Goate AM, Edenberg HJ, Foroud T, Bogdan R, Agrawal A | display-authors = 6 | title = Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans | journal = Genes, Brain and Behavior | volume = 18 | issue = 6 | pages = e12580 | date = July 2019 | pmid = 31099175 | pmc = 6726116 | doi = 10.1111/gbb.12580 }} Additionally, a GWAS study highlighted a significant association between SBK3 and unspecified psychiatric, cognitive, and behavioral traits.Wetherill, L., Lai, D., Johnson, E. C., Anokhin, A., Bauer, L., Bucholz, K. K., ... & Kramer, J.

(2019). Genome‐wide association study identifies loci associated with liability to

alcohol and drug dependence that is associated with variability in reward‐related ventral striatum activity in African‐and European‐Americans. Genes, Brain and Behavior, 18(6), e12580.

In lupus kidney biopsies, SBK3 was shown to have a negative correlation with the expression of CD3 and CD4 T-cell receptors.{{cite journal | vauthors = Pamfil C, Makowska Z, De Groof A, Tilman G, Babaei S, Galant C, Montigny P, Demoulin N, Jadoul M, Aydin S, Lesche R, McDonald F, Houssiau FA, Lauwerys BR | display-authors = 6 | title = Intrarenal activation of adaptive immune effectors is associated with tubular damage and impaired renal function in lupus nephritis | journal = Annals of the Rheumatic Diseases | volume = 77 | issue = 12 | pages = 1782–1789 | date = December 2018 | pmid = 30065042 | pmc = 6241616 | doi = 10.1136/annrheumdis-2018-213485 }} In a study comparing primary tumors and metastatic tumors from the kidney, this gene was found to have at least a two-fold increase in expression in metastatic tumors.{{cite journal | vauthors = Zhao A, Guru A, Guru S, Yang E, Li Y |title=Gene expression in primary and metastatic kidney cancer to discover drivers of metastasis and targets for drug development |journal=Journal for Immunotherapy of Cancer |date=2015 |volume=3 |issue=Suppl 2 |pages=P215 |doi=10.1186/2051-1426-3-S2-P215| pmc=4649392 |doi-access=free }} A pharmacological profiling study identified SBK3 as an inhibitor of fostamanib, an orphan drug for rheumatoid arthritis and immune thrombocytopenic purpura.{{cite journal | vauthors = Rolf MG, Curwen JO, Veldman-Jones M, Eberlein C, Wang J, Harmer A, Hellawell CJ, Braddock M | display-authors = 6 | title = In vitro pharmacological profiling of R406 identifies molecular targets underlying the clinical effects of fostamatinib | journal = Pharmacology Research & Perspectives | volume = 3 | issue = 5 | pages = e00175 | date = October 2015 | pmid = 26516587 | pmc = 4618646 | doi = 10.1002/prp2.175 }}

{{Reflist}}

Category:Enzymes

Category:Genes on human chromosome 19

Category:Human proteins