Ciliated left-right organizer metallopeptidase (CIROP) is a protein that in humans is encoded by the CIROP gene.NCBI GENE report on CIROP https://www.ncbi.nlm.nih.gov/gene/100128908
Gene The CIROP gene is found on the negative strand of the long arm of human chromosome 14 at position 11.2. Its gene neighbors on the negative strand are CEBPE(CCAAT Enhancer Binding Protein Epsilon),Gencards CEBPE entry and ACIN1 (Apoptotic Chromatin Condensation Inducer) 1.Genecards ACIN1 entryNCBI GENE report on CIROP CIROP is 5,928 bp long.Genecards entry on CIROP
Expression CIROP has no tissue specificity with ubiquitous low expression. CIROP is most expressed in the testis, thyroid, and lungs.NCBI RNAseq expression CIROP entry It also goes by the alias LMLN2. CIROP is expressed during the development of the left right organizer in early embryogenesis.Szenker-Ravi, E., Ott, T., Khatoo, M., Moreau de Bellaing, A., Goh, W. X., Chong, Y. L., Beckers, A., Kannesan, D., Louvel, G., Anujan, P., Ravi, V., Bonnard, C., Moutton, S., Schoen, P., Fradin, M., Colin, E., Megarbane, A., Daou, L., Chehab, G., Di Filippo, S., ... Reversade, B. (2022). Discovery of a genetic module essential for assigning left-right asymmetry in humans and ancestral vertebrates. Nature genetics, 54(1), 62–72.
Transcript The mRNA transcript for CIROP is 2656 base pairs long and includes 16 exons.NCBI CIROP Isoform 1 transcript There is a second isoform that excludes exons 5-6 which can be seen underlined in the conceptual translation in figure 2.NCBI CIROP Isoform 2 transcript
Protein The most complete sequence produces a protein that is 788 amino acids long. The protein features a zinc binding domain motif, and 5 N-linked glycosylation sites.MyHits Motif Scan tool Additionally computational analysis predicted six Myristoylation sites, three sumoylation sites, GPS sumoylation tool and one Propionylation site. The CIROP protein is found on the cell membrane with a type 1A transmembrane morphology which can be seen in figure 4 with the N-terminus being extracellular and the c-terminus being cytosolic.PSORT II tool
Protein Interactions CIROp interacts with three cell surface proteins, Ring Finger Protein 225 (RNF225),Genecards RNF225 entry Marker Of Proliferation Ki-67(MKI67),Genecards MKI67 entry and Anthrax Toxin Receptor Like(ANTXRL). Genecards ANTXRL entry RNF225 is predicted to be an important component of the cell membrane and play a role in enabling metal ion binding. MKI67 is involved in mitotic chromosome regulation and c-terminus binding capability. ANTXRL is predicted to be a component of the cell membrane, play a role in toxin transport, and enable the activity of transmembrane signaling receptors.
Evolutionary History CIROP first appeared in cartilaginous jawless fish approximately 563 million years ago. CIROP is in the peptidase M8 family which has 14 other constituents. MEROP peptidase M8 family description
Evolution rate CIROP is evolving quickly at a comparable rate to the fibrinogen alpha chain, as shown in figure 5.
Orthologs CIROP has orthologs in most mammals, amphibians, lungfish, and lampreys. It is not found in pigs, birds, and most whales.Human protein atlas CIROP entry
Paralogs CIROP has one paralog in humans leishmanolysin like peptidase(LMLN) which is also a member of the M8 peptidase family. LMLN is found in all the CIROP orthologs listed in table 1 with the exception being the tasmanian devil(Sarcophilus harrisii). LMLN is found in birds and as far back as cartilaginous fish.LMLN orthologs It also has a paralog called invadolysin found only in arthropods.Invadolysin orthologs
Clinical Significance There are six mutations to CIROP that can be pathogenic causing developmental issues consistent with the disorder Situs ambiguus.MalaCards entry on heterotaxy disorder Knocking out CIROP in zebrafish and Xenopus models also produced similar conditions consistent with Situs Ambiguus.Zvenker-Ravi et al. There is a mutation that can occur in the 3' UTR that disrupts the binding site for the microRNA MiR-7-1 which increased the susceptibility of ischemic strokes in Han Chinese populations.Guo, X., Zhu, L., Zhao, X. et al. Influence of the rs6736 Polymorphism on Ischemic Stroke Susceptibility in Han Chinese Individuals via the Disruption of miR-7–1 Binding to the C14orf119 Gene. J Mol Neurosci 72, 459–467 (2022).
Function CIROP's expression during left-right organizer development and its proclivity to cause situs ambiguus when mutated or knocked out suggests it's an essential protein for left-right organizer function. This and CIROPs morphology on the cell surface points to CIROP playing a key role in regulating the left-right organizer through its cell surface.
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