XK Related 7 (XKR7) is a protein predicted to be a transmembrane protein in Homo sapiens encoded by the XKR7 gene. The primary alias is c20orf159, but it is commonly referred to as XKR7. It is predicted to be involved in apoptotic process during development.
Gene The XKR7 gene is located on plus end strand of chromosome 20 at locus 20q.11.21 and spans from 31968151 to 32003387. It is 1740 base pairs long and contains 3 exons with no known isoforms.
Gene neighbors Several other genes are near the XKR7 gene along chromosome 20. Some of the closest ones are PDRG1, TTLL9, and CCM2L. GeneDescription PDRG1A protein-coding gene near XKR7 in the regulatory-element context of its promoter/enhancer region.TTLL9Also appears in the same regulatory neighborhood as XKR7.CCM2LAnother gene near XKR7 whose protein interacts with XKR7
Gene level regulation XKR7 is expressed in the brain and pancreas, but lowly at around fifteen percent. The multiple sequence alignment of XKR7 and it's orthologs showed high conservation of the 5' untranslated region where transcription factor ZNF460 binds too.
Protein The XKR7 protein contains 579 amino acids with a molecular weight of 63 kDa, and consists of 3 disordered regions, alongside 6 transmembrane regions. XKR7 was found to have high amounts of these amino acids: Leu,Val, Ile, Phe, and Met; all of which contribute to transmembrane helices. There are no major charge clusters, showing no strong cytoplasmic regulatory domains. However, the isoelectric point is 9.2, so at lower pHs, XKR7 will be positively charged.
Structure
The tertiary structure of XKR7 mostly consists of alpha helices. The most confident parts of the structure is the transmembrane region, which is highly hydrophobic and uncharged. The disordered regions are shown by red and blue, which consists of cations and anions, and is hydrophilic.
Protein level regulation There are around 7 phosphorylation sites between 2nd and 3rd transmembrane protein. Analysis on the mouse ortholog produces the exact same image with these phosphorylation sites conserved: S154, G167, T183, Y201, S206, S240, and S249. Y201 is the most functionally important site. When Y201 is phosphorylated, it’s a binding site for SH2-domain proteins (docking site), and when it’s unphosphorylated it functions as a tyrosine-based sorting signal for adaptor proteins.
Protein - protein interactions
CCM2L and PGBD5 have the highest interaction scores. Using co-IP or pull-down assays could test physical binding. Using fluorescence microscopy would verify whether the proteins are in the same cellular compartment. Abbreviated nameFull NameScoreSubcellular Compartment FunctionCCM2LCerebral cavernous malformations 2 protein-like0.628Membrane associatedRegulates signaling and cell-cell junctionsPGBD5PiggyBac transposable element-derived protein 50.608Nucleus Influences genome regulation in neuronsCCDC137Coiled-coil domain containing 1370.529Nucleus/NucleolusNucleolar organizationZC3H3Zinc finger CCCH domain-containing protein 30.501NucleusRegulates RNA processing
Single nucleotide polymorphisms Most of the SNPs were found towards the C-term, transmembrane regions, or disordered regions. Order in CTSNPChangeBase ChangeMutation TypeSignificance 1rs138804760Met417ThrT → CmissenseTMR 7 2rs147437006Arg292Glu Arg292LeuG → A,TmissenseN/A3rs200124372Arg483Glu Arg483Pro Arg483LeuG → A,C,TmissenseIn disordered region 4rs367920055Thr558Lys Thr558MetC → A,TmissenseC-term5rs371260952Asp374LysC → A,Tmissense or silentTMR 66rs541196906Arg565Glu Arg565Pro Arg565LeuG → A,C,TmissenseC-term7rs546872871Ala161Met Ala161Val Ala161LeuC → A,G,TmissenseIn disordered region8rs572256162Val233TyrG → AmissenseC-term
Homology +Paralogs of XKR7 Homo SapiensParalogAmino Acid LengthPercent SimilarityPercent IdentityHSA_XKR465057%46%HSA_XKR664156.3%44.60%HSA_XKR839533.10%22.30%HSA_XKR9_237330.70%18.10%HSA_XKR5_168626.40%18.10%HSA_XKR5_252316.20%11.00%HSA_XKR9_124119.80%12.80% XKR7 in Homo Sapiens has many paralogs as it’s a part of a very large X-Kell related protein family. The XKR protein family primarily functions as lipid scramblases, a crucial protein to signal for apoptosis. There are a total of seven paralogs with the two most similar to XKR7 are XKR4 and XKR6 (Ref. Paralog table). Paralogs were found using Genecards and NCBI Protein database, while the sequence similarity and identity were done through Emboss Needle. +Orthologs of XKR7 Homo SapiensGenus and speciesCommon NameTaxonomic GroupMedian Date of Divergence (MYA)Accession NumberAmino Acid Sequence LengthSequence Identity to Human ProteinSequence Similarity to Human ProteinHomo sapiensHumansPrimates0NP_001011718.1579100%100%Sarcophilus harrisiiTasmanian devilDasyuromorphia160XP_02336311157172%78.10%Gracilinanus agilisAgile gracile opossumDidelphimorphia160XP_04451571762576%75.00%Opisthocomus hoazinHoazinOpisthocomiformes319XP_07529451954568%75.40%Excalfactoria chinensisKing quailGalliformes319XP_07220662952768%75%Malaclemys terrapinDiamondback terrapinTestudines319XM_054046095.157770%79.60%Podarcis raffoneiAeolian wall lizardSquamata319XP_05324770357472%75.60%Erythrolamprus reginaeRoyal ground snakeSquamata319XP_07060037059066.70%75.60%Chelonoidis abingdoniiPinta Island tortoiseTestudines319XP_07492854358167.30%75.00%Pleurodeles waltlIberian ribbed newtUrodela352XP_06909947753166%74.70%Microcaecilia unicolorGymnophiona352XP_030069193.156264%72.40%Phyllobates terribilisGolden poison frogDendrobatidae352XP_07353893349462%67.70%Conger congerEuropean congerAnguilliformes429XP_06111455656763%73.40%Polypterus senegalusGray bichirPolypteriformes429XP_03959070655463%72.10%Erpetoichthys calabaricusReedfishPolypteriformes429XP_02866749755463%71.90%Semicossyphus pulcherCalifornia sheepheadPerciformes429XP_06951559661156%68.30%Callorhinchus miliiAustralian ghostsharkHolocephali462XP_04219780154961%68.30%Chiloscyllium punctatumBrownbanded bamboo sharkOrectolobiformes462XP_07241286259560%71.60%Hemitrygon akajeiRed stingrayMyliobatiformes462XP_07291796057459%70.80%Amblyraja radiataThorny skateRajiformes462XP_03289712458164%70.30%Petromyzon marinusSea lampreyPetromyzontiformes563XP_07592975375253%47.60% Orthologs of XKR7 Homo sapiens are sorted by median date of divergence and then by sequence identity to XKR7 Homo sapiens. There were an overwhelming number of mammal, avian, and reptilian orthologs, but the number of orthologs decreased as the median date of divergence increased. Actinopterygii and Chondrichthyes both only had a handful of orthologs for XKR7 Homo sapiens, but it mostly consisted of orthologs for XKR7 Homo sapiens paralogs. Sequences, identity, and similarity were found using NCBI Protein and Emboss Needle.Cyclostomata, Jawless fish, are the most distantly related species to humans with the Sea Lamprey having a median date of divergent of 563 million years ago and 53% identity. Marsupials, Avians, Reptilia, with average sequence identity of 73.6% sequence identity.
Clinical significance It is suggested, using mouse shotgun data alongside humans, could hold the key to understanding diseases like Creutzfeldt-Jakob disease, a rare and fatal neurodegenerative disease from an accumulation of prions, and severe immunodeficiency. A study by Zhang et al. (2020) used RNA-seq for comparative expression in small cell lung cancer (SCLC) and adjacent normal tissue, which identified DRD2 and XKR7 upregulating SCLC. Such a significant difference suggests that XKR7 could be linked to greater tumor aggressiveness. Gnathodiaphyseal Dysplasia is also associated with XKR7, but it's not the main cause.
References