View source for KRBA1

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{infobox_gene}}
'''KRBA1''' is a [[protein]] that in humans is encoded by the KRBA1 [[gene]].  It is located on the plus strand of chromosome 7 from 149,411,872 to 149,431,664.<ref name=":0">{{Cite web|title=AceView: Gene:KRBA1, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView.|url=https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&q=KRBA1|website=www.ncbi.nlm.nih.gov|access-date=2020-05-02}}</ref> It is also commonly known under two other aliases: KIAA1862 and KRAB A Domain Containing 1 gene and encodes the KRBA1 protein in humans.<ref>{{Cite web|title=KRBA1 Gene - GeneCards {{!}} KRBA1 Protein {{!}} KRBA1 Antibody|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=KRBA1|website=www.genecards.org|access-date=2020-05-02}}</ref> The KRBA family of genes is understood to encode different transcriptional repressor proteins<ref name=":1">{{Cite web|title=CDD Conserved Protein Domain Family: KRAB_A-box|url=https://www.ncbi.nlm.nih.gov/Structure/cdd/cl02581|website=www.ncbi.nlm.nih.gov|access-date=2020-05-02}}</ref>
== Gene ==
[[File:KRBA1 gene location.png|thumb|Location of KRBA1 Gene on chromosome 7 as designated by the red line|372x372px]]
The KRBA1 gene is located on [[chromosome]] 7 at 7q36 in humans. It is 3786 base pairs in length with 17 [[exon]]s total, however the coding sequence is only 3196 base pairs long resulting in a protein with 1064 [[amino acid]]s.<ref name=":2">{{Cite web|title=KRBA1 KRAB-A domain containing 1 [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene?cmd=retrieve&list_uids=84626|website=www.ncbi.nlm.nih.gov|access-date=2020-05-02}}</ref>
== Protein ==
The KRBA1 protein has a predicted [[isoelectric point]] of 7.8pI and a predicted molecular weight of 112 kD which makes it a relatively large and neutral protein.<ref name=":3">{{Cite web|title=ExPASy - Compute pI/Mw tool|url=https://web.expasy.org/compute_pi/|website=web.expasy.org|access-date=2020-05-02}}</ref> This [[protein]] is primarily made up of four amino acids. The four major ones are: [[Proline]] at 15.7%, [[Glycine]] at 11.2%, [[Serine]] at 10.9%, and [[Leucine]] at 10.2%.<ref name=":3" /> Proline is present in well above average proportions. However, it was the only one as such and the amino acids M, N, Y, I, and F are all present in just below average proportions.
=== Isoforms ===
There are two isoforms for this protein known simply as isoform 1 and 2. Isoform 1 is the smaller one as it has a shorter N-terminus. Additionally, its 5'-UTR is different and its start codon is farther downstream.<ref name=":2" />
=== Domains and motifs ===
The domain of function is the [[Krüppel associated box|KRBA box]] which is predicted to start at base pair 7 and end at base pair 47. For motifs there was a [[leucine zipper]] and two [[Nuclear localization sequence|nuclear localization signals]] (NLS) were found.<ref name=":4">{{Cite web|title=PSORT II Prediction|url=https://psort.hgc.jp/form2.html|website=psort.hgc.jp|access-date=2020-05-02}}</ref> Additionally, two fairly large proline rich regions are present towards the [[C-terminus]] of the protein.<ref>{{Cite web|title=ELM - Search the ELM resource|url=http://elm.eu.org/|website=elm.eu.org|access-date=2020-05-02}}</ref>
The leucine zipper is present at base pair 837: LHSLGAALAEKLDRLATALAGL
One 4 pattern and one 7 pattern NLS were found
pat4: KRPR @ 763bp
pat7: PSRRKSH @ 217bp
=== Secondary and tertiary structure ===
Using the [[GOR method|GOR4]] program, it can be inferred that KRBA1 has very little specific [[Protein secondary structure|secondary structure]] composed of mostly random coil regions. Random coil regions constitute 75.00% of the protein, while alpha helices constitute 16.26% and extended strands 8.74%.<ref>{{Cite web|title=NPS@ : GOR4 secondary structure prediction|url=https://npsa-prabi.ibcp.fr/cgi-bin/npsa_automat.pl?page=/NPSA/npsa_gor4.html|website=npsa-prabi.ibcp.fr|access-date=2020-05-02}}</ref> The alpha helices are broken up into many sections throughout the protein.
== DNA level regulation ==
=== Promoter ===
The promoter region was chosen using ElDorado at Genomatix, which assessed the KRBA1 gene locus for possible promoter regions. Out of nine possible promoter sets, Promoter Set 2 (GXP_660502) was chosen, as its transcripts had much higher numbers of CAGE tags than any other set. Coding transcript GXT_27212195 was used, as it had the highest number of exons (17/17 possible), and matched with the NM_001290187 accession number on NCBI for KRBA1 mRNA.<ref name=":5">{{Cite web|title=Genomatix - NGS Data Analysis & Personalized Medicine|url=https://www.genomatix.de/?s=14e3197a7642d3f12be8bd8a30214856|website=www.genomatix.de|access-date=2020-05-02}}</ref>
=== Transcription factor binding sites ===
{| class="wikitable sortable mw-collapsible"
|+As determined by MatInspector at Genomatix, the following are [[transcription factor]]s (TFs) predicted to bind to KRBA1 in the promoter region. They were selected based on increased similarity scores and increased occurrences.<ref name=":5" />
!Matrix Family
!Detailed Family Information
!Matrix
!Detailed Matrix Information
!Starting bp
!Ending bp
!Anchor bp
!Strand
!Similarity
!Sequence
|-
|V$ZTRE
|Zinc transcriptional  regulatory element
|V$ZTRE.03
|5' half site of ZTRE  motif
|1141
|1157
|1149
|(+)
|0.993
|ccCTCCccctcggccca
|-
|V$ZTRE
|Zinc transcriptional  regulatory element
|V$ZTRE.03
|5' half site of ZTRE  motif
|898
|914
|906
|(-)
|0.989
|ccCTCCcctcgtccccg
|-
|V$ZTRE
|Zinc transcriptional  regulatory element
|V$ZTRE.04
|3' half site of ZTRE  motif
|1133
|1149
|1141
|(-)
|0.984
|gggGGAGgggcgggggt
|-
|V$ZTRE
|Zinc transcriptional  regulatory element
|V$ZTRE.04
|3' half site of ZTRE  motif
|906
|922
|914
|(+)
|0.983
|aggGGAGggggcgggga
|-
|V$PLAG
|Pleomorphic adenoma  gene
|V$PLAG1.01
|Pleomorphic adenoma  gene (PLAG) 1, a developmentally regulated C2H2 zinc finger protein
|66
|88
|77
|(+)
|0.951
|cgGAGGccgggacgaggggttgt
|-
|V$PLAG
|Pleomorphic adenoma  gene
|V$PLAG1.02
|Pleomorphic adenoma  gene 1
|307
|329
|318
|(-)
|1
|aaGGGGgcctgcggggctaagcc
|-
|V$PLAG
|Pleomorphic adenoma  gene
|V$PLAG1.02
|Pleomorphic adenoma  gene 1
|459
|481
|470
|(+)
|1
|caGGGGgaggcagaggagagtgg
|-
|V$PLAG
|Pleomorphic adenoma  gene
|V$PLAG1.02
|Pleomorphic adenoma  gene 1
|30
|52
|41
|(+)
|1
|gaGGGGgctttgcccgagtgggc
|-
|V$SMAD
|Vertebrate SMAD  family of transcription factors
|V$SMAD3.01
|Smad3 transcription  factor involved in TGF-beta signaling
|199
|209
|204
|(+)
|0.994
|gctGTCTgggc
|-
|V$SMAD
|Vertebrate SMAD  family of transcription factors
|V$SMAD3.01
|Smad3 transcription  factor involved in TGF-beta signaling
|213
|223
|218
|(+)
|0.996
|aagGTCTggac
|-
|V$SMAD
|Vertebrate SMAD  family of transcription factors
|V$SMAD3.01
|Smad3 transcription  factor involved in TGF-beta signaling
|428
|438
|433
|(-)
|0.994
|ctgGTCTgggc
|-
|V$SMAD
|Vertebrate SMAD  family of transcription factors
|V$SMAD3.02
|Smad3 transcription  factor involved in TGF-beta signaling factor PU.1
|363
|373
|368
|(-)
|0.993
|cctGTCTggag
|-
|V$AHRR
|AHR-arnt  heterodimers and AHR-related factors
|V$AHRARNT.03
|DRE (dioxin response  elements), XRE (xenobiotic response elements) bound by AHR/ARNT heterodimers
|41
|65
|53
|(+)
|0.971
|gcccgagtggGCGTgcgcctttcct
|-
|V$AHRR
|AHR-arnt  heterodimers and AHR-related factors
|V$AHRARNT.03
|DRE (dioxin response  elements), XRE (xenobiotic response elements) bound by AHR/ARNT heterodimers
|246
|270
|258
|(+)
|0.952
|agtctcctctGCGTgggaccacagc
|-
|V$AHRR
|AHR-arnt  heterodimers and AHR-related factors
|V$AHRARNT.01
|Aryl hydrocarbon  receptor / Arnt heterodimers
|556
|580
|568
|(-)
|0.97
|gtcacattttgCGTGcctgtttgct
|-
|V$AHRR
|AHR-arnt  heterodimers and AHR-related factors
|V$AHRARNT.03
|DRE (dioxin response  elements), XRE (xenobiotic response elements) bound by AHR/ARNT heterodimers
|658
|682
|670
|(-)
|0.956
|gtccggccggGCGTgggtgggacag
|}
=== Expression pattern ===
In humans, this gene is ubiquitously expressed at a fairly low level, approximately 0.6 times the expression of the average gene.<ref name=":2" /> Keeping that in mind, this gene is expressed the most in the heart. There is some expression in other areas such as the reproductive organs and the brain, but it is much less. When it comes to the common mouse ''Mus musculus'', the expression of the KRBA1 gene occurs in different areas of the body compared to humans. In mice, the highest expression isn't in the heart but in the reproductive organs along with the adrenal gland and thymus.<ref name=":2" />
== Protein level regulation ==
=== Localization ===
This protein is localized in the nucleus.<ref name=":0" /> The gene is predicted to contain two nuclear localization signals (NLS) both a 4 residue pattern and 7 residue pattern signal.<ref name=":4" />
=== Post translational modifications ===
There weren't many different types of post translational modifications that were found. However, the few that were found occur throughout the protein at high levels. The few that were found were: [[O-Linked β-N-acetylglucosamine|O-GlcNAc]],<ref>{{Cite web|title=YinOYang 1.2 Server|url=http://www.cbs.dtu.dk/services/YinOYang/|website=www.cbs.dtu.dk|access-date=2020-05-02}}</ref> [[O-linked glycosylation|O-Glycosylation]],<ref>{{Cite web|title=NetOGlyc 4.0 Server|url=http://www.cbs.dtu.dk/services/NetOGlyc/|website=www.cbs.dtu.dk|access-date=2020-05-02}}</ref> and [[Protein phosphorylation|net phosphorylation]],<ref>{{Cite web|title=NetPhos 3.1 Server|url=http://www.cbs.dtu.dk/services/NetPhos/|website=www.cbs.dtu.dk|access-date=2020-05-02}}</ref> and [[glycation]].<ref>{{Cite web|title=NetGlycate 1.0 Server|url=http://www.cbs.dtu.dk/services/NetGlycate/|website=www.cbs.dtu.dk|access-date=2020-05-02}}</ref> All four of them have a multitude of sites throughout the entire protein.
== Homology and evolution ==
[[File:KRBA1 Evolution Graph.png|thumb|264x264px|The mutation rate of KRBA1 compared to [[fibrinopeptide]]s, hemoglobin, and cytochrome c.]]
KRBA1 orthologs have a relatively high mutation rate as seen in the graph below comparing KRBA1 with [[fibrinopeptide]]s, hemoglobin, and cytochrome C. The orthologs in the table below are sorted by sequence identity and similarity.<ref name=":2" />
{| class="wikitable sortable"
|+This table displays 10 relatively distant orthologs with sequence identity ranging from 63%-36%<ref name=":2" /><ref>{{Cite web|title=TimeTree :: The Timescale of Life|url=http://www.timetree.org/|website=www.timetree.org|access-date=2020-05-03}}</ref>
|Genus and Species
|Common name
|Taxonomic Group
|Date of divergence
(MYA)
|Accession number
|Sequence length (aa)
|Sequence identity %
|Sequence similarity
|-
|[[Homo sapiens]]
|Humans
|[[primate]]s
|n/a
|NP_001277116.1
|1064
|100%
|100%
|-
|[[Asinus|Equus asinus]]
|Asinus
|[[Equidae]]
|96
|XP_014686007.1
|1179
|63%
|69%
|-
|[[Weddell seal|Leptonychotes weddellii]]
|Weddell seal
|[[Pinniped]]ia
|96
|XP_030881320.1
|1142
|63%
|69%
|-
|[[Harbor seal|Phoca vitulina]]
|Harbor seal
|Pinnipedia
|96
|XP_032257255.1
|1184
|63%
|69%
|-
|[[Greater mole-rat|Nannospalax galili]]
|Greater mole rat
|[[Rodent]]ia
|90
|XP_008832018.1
|1103
|62%
|69%
|-
|[[Cat|Felis catus]]
|Cat
|[[Felidae]]
|96
|XP_011278956.2
|1159
|62%
|67%
|-
|[[House mouse|Mus musculus]]
|Mouse
|Rodentia
|90
|NP_001334081.1
|1078
|58%
|67%
|-
|[[Gairdner's shrewmouse|Mus Pahari]]
|Garidner's shrewmouse
|Rodentia
|90
|XP_029390880.1
|1086
|57%
|66%
|-
|[[Red junglefowl|Gallus gallus]]
|Chicken
|[[Bird|Aves]]
|312
|XP_025003155.1
|555
|40%
|52%
|-
|[[Central bearded dragon|Pogona vitticeps]]
|Central bearded dragon
|[[Reptile|Reptilia]]
|312
|XP_020655832.1
|1697
|36%
|51%
|}
[[File:KRBA1 Tree.png|thumb|This picture depicts a time-calibrated, unrooted, phylogenetic tree of a few organisms that have orthologs of the KRBA1 gene.|307x307px]]
== Function and biochemistry ==
The domain of function on this gene is known as the KRAB (Kruppel-associated box) domain - A box and it spans from amino acid 7 to 47. It is a transcription repression domain within the zinc finger proteins subgroup of the KRAB-ZFPs family.<ref name=":1" /> The KRAB domain interacts with and recruits other proteins and corepressors and then represses transcription. The mechanism appears to be the following: the KRBA proteins via their KRAB domain recruit the repressor KAP1 (KRAB-associated protein-1, also known as transcription intermediary factor 1 beta, KRAB-A interacting protein). The KAP1/ KRAB complex then recruits the heterochromatin protein 1 (HP1), and other chromatin modulating proteins, leading to transcriptional repression through heterochromatin formation.<ref name=":1" />
== Interacting proteins ==
Using the STRING database, two interacting proteins were found to have high confidence interaction scores. High interaction scores are any scores above 0.7. The two proteins are Transcription intermediary factor 1-beta ([[TRIM28]]) with a score of 0.903 and Leucine-rich repeat-containing protein 61 (LRRC61) with a score 0.803.<ref>{{Cite web|title=KRBA1 protein (human) - STRING interaction network|url=https://version11.string-db.org/cgi/network.pl?taskId=xKw7HUvfVj8S|website=version11.string-db.org|access-date=2020-05-02}}</ref>
== Clinical significance ==
A research done by Zaibo Li et al. displayed the KRAB-A-Domain in action. The von-Hippel Lindau tumor suppressor (pVHL) is a part of protein complex known as E3 ubiquitin ligase and targets hypoxia-inducible-factor 1a (HIF-1a) for breakdown. It is reported that there is a new protein that was discovered that interacts with the pVHL protein and helps it with its job.<ref name=":6">{{cite journal | vauthors = Li Z, Wang D, Na X, Schoen SR, Messing EM, Wu G | title = The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity | journal = The EMBO Journal | volume = 22 | issue = 8 | pages = 1857–67 | date = April 2003 | pmid = 12682018 | pmc = 154465 | doi = 10.1093/emboj/cdg173 }}</ref> pVHL works by bringing in histone deacetylases, and it is helped by a certain domain on this new protein. It is shown in a study by Li et al. that this domain is the KRAB-A-domain and it mediates pVHL's transcriptional repression of HIF-1a.<ref name=":6" /> Additionally, the research shows that the KRAB-A-domain is shown to repress transcription on top of its ability to recruit histone deacetylases.<ref name=":6" />
== References ==
<references />
[[Category:Genes on human chromosome 7]]