Glutamate-rich protein 4 is a protein which in humans is encoded by the gene ERICH4 (previously C19orf69). ERICH4 is highly conserved in mammals and exhibits overexpression in tissues of the kidneys, terminal ileum, and duodenum. The function of ERICH4 has yet to be well understood by the scientific community.
Gene ERICH4 is located on the sense strand of 19q13.2 in humans, consists of 2,340 base pairs, and contains 2 exons. ERICH4, on the sense strand, is located within DMAC2 and next PCAT19 and B3NT8 which are all on the antisense strand.
Promoter & Predicted Transcription Factors (TF) The promoter is predicted to begin 1,806 bp upstream from the 5' UTR and consists of 1,819 bp which overlaps with the coding sequence by 13 bp.
Matrix ID TF Name Genomic Position with Human ERICH4 Promoter Strand of q19 Matrix Similarity Literature Supported Function V$CEBPA.01 CCAAT/Enhancer-binding Protein Alpha 41,441,752-41,441,766 Sense (+) 0.962 Recruit co-activators that in turn can open up chromatin structure or recruit basal transcription factors. O$VTATA.01 Vertebrate TATA-binding Factor 41,442,466-41,442,482 Antisense (-) 0.915 Required for initiation of transcription and is associated with a variety of different transcription factors. V$SOX1.04 SRY (Sex Determining Region)-Box 1 41,442,480-41,442,502 Sense (+) 0.801 Involved in the regulation of embryonic development and in the determination of the cell fate. V$HSF1.04 Heat Shock Factor 1 41,442,536-41,442,560 Sense (+) 0.769 Activation in cellular stress. V$BTEB3.01 Krueppel-like Factor 13 (KLF13) 41,442,243-41,442,261 Sense (+) 0.934 KLF13 knock-out mice show a defect in lymphocyte survival as KLF13 is a regulator of Bcl-xL expression. V$PAX5.01 B-cell Specific Activator Protein 41,442,955-41,442,983 Sense (+) 0.796 Key role in B-lymphocyte development. V$GLI3.02 GLI-Kruppel Family Member GLI3 41,443,115-41,443,131 Sense (+) 0.915 Thought to play a role during embryogenesis. V$NR2F6.01 Nuclear Receptor subfamily 2 group F member 6 (NR2F6) 41,442,507-41,442,531 Sense (+) 0.851 Transcriptional repressor of IL17 expression in Th17-differentiated CD4-positive T cells in-vitro and in-vivo. V$MAFB.01 MAFB/Leucine Zipper Transcription Factor 41,442,601-41,442,625 Sense (+) 0.923 Regulation of lineage-specific hematopoiesis. Represses ETS1-mediated transcription of erythroid-specific genes in myeloid cells. V$AP4.03 Activating Enhancer Binding Protein 4 (TFAP4) 41,443,003-41,443,019 Sense (+) 0.993 Regulates the expression of genes involved in the regulation of cellular proliferation, stemness, and epithelial-mesenchymal transition. V$EVI1.05 Ecotropic Viral Integration Site 1 (EVI1) Encoded Factor 41,442,583-41,442,599 Sense (+) 0.821 Regulation of hematopoietic stem cell renewal. Controls several aspects of embryonic development. V$MRE.01 Mineralcorticoid Receptor Response Element 41,442,844-41,442,862 Sense (+) 0.939 Involved in water electrolyte homeostasis, blood pressure regulation, inflammation, and fibrosis in the renocardiovascular system. V$ARE.03 Androgene Receptor Binding Site, IR3 Sites 41,442,844-41,442,862 Antisense (-) 0.946 Ligand-dependent transcription factor that controls the expression of specific genes. The binding of the AR to its native ligands 5α-dihydrotestosterone (DHT) and testosterone initiates male sexual development and differentiation. V$ZNF217.01 Zinc Finger Protein 217 41,443,023-41,443,035 Sense (+) 0.911 Promotes cell proliferation and antagonizes cell death. V$RORA.02 RAR-related Orphan Receptor Alpha, Homodimer DR5 Binding Site 41,442,783-41,442,807 Sense (+) 0.831 Possible role in lymphocyte development. Possible function in negatively regulating inflammation due to a report of positive relation in the expression of IKBa, a negative regulator of the NF-kB signaling pathway. V$STAT6.01 Signal Transducer and Activator of Transcription 6 (STAT6) 41,443,042-41,443,060 Sense (+) 0.961 Plays a central role in exerting IL4-mediated responses. V$ZF5.01 Zinc Finger/POZ Transcription Factor 41,442,874-41,442,888 Sense (+) 0.957 Role in development, oncogenesis, apoptosis, and transcription repression.
mRNA
The ERICH4 mRNA sequence is 955 nucleotides in length with a fold energy predicted as -139.80 kcal/mol with -0.258 energy/base.
Alternative Splicing ERICH4 has one different protein-encoding transcript variant, or isoform.
Name mRNA Length (bp) Protein Length (aa) Mass (Da) Glutamate-rich protein 4 955 130 14,447 Glutamate-rich protein 4 isoform X1 1741 155 N/A
Protein General Properties The primary encoded protein consists of 130 amino acids and has a predicted molecular mass of 14.5 kDa and isoelectric point of 4 pI. As suggested by the protein's name, glutamate-rich protein 4, the protein is most highly composed of glutamic acid amino acids at 17.7% of the protein's composition followed by leucine at 14.6%, and then proline at 9.2%. ERICH4 has no positive or negative charge clusters. The human protein has one identifiable mixed cluster from amino acid 91 to 116 with 3 positively-charged, 15 negatively-charged, and 8 neutral amino acids. The same mixed cluster region in humans is frequently negative within ERICH4's orthologous proteins. This protein contains no significant hydrophobic or transmembrane segments which are supported with comparison to five of ERICH4's orthologs (Graymouse lemur, Sheep, House mouse, African elephant, and Opossum).
Domains ERICH4 has one identified domain of unknown function, DUF4530, which is found in eukaryotes. Proteins in this family are typically 140 amino acids in length and ERICH4 is a known human member of this family.
Secondary Structure A cross-program analysis determines ERICH4 protein to be composed of five separated alpha helixes and five interspersing coils. The alpha helix segments span from amino acids 2-9, 21-24, 47-58, 61-94, and 104-111 in the protein sequence. ERICH4 is not predicted to contain beta-sheets.
Tertiary Structure Program analysis in SWISS-Model proposes a tertiary structure for ERICH4 by matching the protein against the template of NLRP6 with a sequence identity of 25.79%, sequence similarity of 0.30, and coverage of 0.43 for amino acids 43-92 in ERICH4.
Post-translational Regulation ERICH4 has proposed phosphorylation at serine amino acids 28 and 96 and amino acid 36, a threonine, by casein kinase II and protein kinase c, respectively. ERICH4 is not predicted to be undergo a methionine cleavage or acetylation.
Localization This protein is predicted to be intracellular without any transmembrane regions. Sub-cellular localization is predicted to be mostly localized to the cytoplasm with a reliability score of 70.6 via the Reinhardt's method. No significant O-GlcNAc site and N-myristoylation predictions.
Tissue Expression ERICH4’s highest levels of expression are within human tissue of the duodenum and small intestine, followed by the kidneys. Notably, expression within the small intestines is highest in the twentieth week of human fetal development. Within a representative set of mouse (Mus musculus) tissues, Erich4 is most highly expressed within the kidneys, followed by and in decreasing expression, the large intestines, adult duodenum, and adult small intestine. The Sigma-Aldrich antibody product, HPA042632, derived from rabbit, has a strong granular cytoplasmic positivity in cytoplasmic structure in glandular cells (goblet cells) of the rectum.
Abnormal Tissue Expression ERICH4 has high expression within normal tissue and low-to-medium expression with renal cell carcinoma tissue.
An analysis examining ERICH4 was reviewed in tissues of the ileum and colon that were either normal or afflicted with Crohn's disease or ulcerative colitis. ERICH4 had high (~90%) expression within the ileum for all states (normal/control, Crohn's disease, and ulcerative colitis). ERICH4 also has a higher expression in Crohn's disease than in either normal tissue or ulcerative colitis.
Function The function of ERICH4 has yet to be well understood by the scientific community and therefore, requires further research.
Interactions According to STRING analysis, ERICH4 has multiple predicted interactions with other proteins including proteins with associated immune function and expression within the gastrointestinal tract or testes from textmining. No experimentally confirmed protein interactions yet.
Predicted Partner Protein Score Associated Functions Tetratricopeptide Repeat Domain 29 (TTC29) 0.680 Shown to be significantly upregulated during wound healing of human masticatory mucosa. Transmembrane Protein 184A (TMEM184A) 0.552 Functions as a heparin receptor and mediates anti-inflammatory responses of ECs involving decreased JNK and p38 activity. Insulin-like Growth Factor binding protein Acid Labile Subunit (IGFALS) 0.509 Serum protein that binds insulin-like growth factors, increasing their half-life and their vascular localization. Serine Peptidase Inhibitor, Kazal type 4 (SPINK4) 0.500 Has been shown to exhibit Celiac disease pathology-related differential gene expression, likely derived from altered goblet cell activity. Protein Disulfide-Isomerase-Like protein of the Testis (PDILT) 0.497 Catalyzes protein folding and thiol-disulfide interchange reactions. This protein lacks oxidoreductase activity in vitro and is suspected to function as a chaperone.
Homology Paralogs No human paralogs were found for the gene.
Orthologs Orthologs have been identified in most mammals for which complete genome data is available. Notably, ERICH4 orthologs are only present in placental and marsupial mammals but absent in monotremes. The most distant ortholog was identified in the gray short-tailed opossum which is a marsupial mammal.
No significant similarities were found in the vertebrates Aves, Reptilia, Amphibia, Chondrichthyes, Osteichthyes or Agnatha. Searching to exclude vertebrates in BLAST and BLAT produced no significant ortholog findings for invertebrates, fungi, and bacteria.
Species Common name NCBI Accession Number Sequence length (AA) Millions of Years since LCA % Identity % Similarity Taxonomic group Homo sapiens Human NP_001123986.1 130 --- 100 100 Primates Microcebus murinus Gray mouse lemur XP_012616209.1 179 73 72 80 Primates Tupaia chinensis Northern treeshrew XP_006165343.1 137 85 63 72 Scandentia Mus pahari Gairdner's shrewmouse XP_021075502.1 141 88 57 63 Rodentia Meriones unguiculatus Mongolian gerbil XP_021519873.1 141 88 60 64 Rodentia Rattus norvegicus Brown rat NP_001102923.1 147 88 61 65 Rodentia Mus musculus House mouse NP_001034332.2 140 88 62 71 Rodentia Microtus ochrogaster Prairie vole XP_005361243.1 140 88 62 71 Rodentia Erinaceus europaeus European hedgehog XP_007536664.1 129 94 61 68 Eulipotyphla Orcinus orca Killer whale XP_004271419.2 121 94 62 72 Cetacea Physeter catodon Sperm whale XP_007128192.1 121 94 64 72 Cetacea Desmodus rotundus Common vampire bat XP_024433457.1 180 94 66 73 Chiroptera Ovis aries Sheep XP_012045823.2 131 94 69 75 Artiodactyla Bos taurus Cattle XP_002695042.1 131 94 69 75 Artiodactyla Pteropus alecto Black flying fox XP_006910763.1 133 94 71 78 Chiroptera Hipposideros armiger Great roundleaf bat XP_019488166.1 134 94 71 79 Chiroptera Loxodonta africana African bush elephant XP_003420798.1 127 102 58 66 Proboscidea Monodelphis domestica Gray short-tailed opossum XP_007492011.1 106 160 45 61 Didelphimorphia Phascolarctos cinereus Koala XP_020834126.1 109 160 48 63 Diprotodontia Vombatus ursinus Common wombat XP_027701859.1 109 160 49 64 Diprotodontia
Molecular Evolution