CIROP gene

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Ciliated left-right organizer metallopeptidase (CIROP) is a protein that in humans is encoded by the CIROP gene.[1]

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),[2] and ACIN1 (Apoptotic Chromatin Condensation Inducer) 1.[3][4] CIROP is 5,928 bp long.[5]

Location of CIROP on chromosome 14 and its gene neighbors

Expression

CIROP has no tissue specificity with ubiquitous low expression. CIROP is most expressed in the testis, thyroid, and lungs.[6] It also goes by the alias LMLN2. CIROP is expressed during the development of the left right organizer in early embryogenesis.[7]

Transcript

The mRNA transcript for CIROP is 2656 base pairs long and inclues 16 exons.[8] There is a second isoform that excludes exons 5-6 which can be seen underlined in the conceptual translation in figure 2.[9]

Conceptual translation of CIROP including major features, post translational modifications, and important mutations

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.[10] Additionally computational analysis predicted six Myristoylation sites, three sumoylation sites,[11] and one Propionylation site. The CIROP protein is found on the cell membrane with a type 1A transmembrane morphology whicch can be seen in figure 4 with the N-terminus being extracellular and the c-terminus being cytosolic.[12]

Protter visualization of CIROP gene with predicted transmembrane morphology
Annotated CIROP predicted protein with N-terminus, C-terminus, Zinc binding domain, and transmembrane domain highlighted[13][14][15]

Protein Interactions

CIROp interacts with three cell surface proteins, Ring Finger Protein 225 (RNF225),[16] Marker Of Proliferation Ki-67(MKI67),[17] and Anthrax Toxin Receptor Like(ANTXRL).[18] 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.[19]

Evolution rate

CIROP is evolving quickly at a comparable rate to the fibrinogen alpha chain, as shown in figure 5.

Evolution rate of Gene CIROP in comparison To Cytochrome C and Fibrinogen alpha

Orthologs

CIROP has orthologs in most mammals, amphibians, lungfish, and lampreys. It is not found in pigs, birds, and most whales.[20]

twenty orthologs for the CIROP gene

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.[21] It also has a paralog called invadolysin found only in arthropods.[22]

Clinical Significance

There are six mutations to CIROP that can be pathogenic causing developmental issues consistent with the disorder Situs ambiguus. [23] Knocking out CIROP in zebrafish and Xenopus models also produced similar conditions consistent with Situs Ambiguus.[24] 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.[25]

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.

References

  1. ^ NCBI GENE report on CIROP https://www.ncbi.nlm.nih.gov/gene/100128908
  2. ^ Gencards CEBPE entry[1]
  3. ^ Genecards ACIN1 entry[2]
  4. ^ NCBI GENE report on CIROP [3]
  5. ^ Genecards entry on CIROP [4]
  6. ^ NCBI RNAseq expression CIROP entry[5]
  7. ^ 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. [6]
  8. ^ NCBI CIROP Isoform 1 transcript [7]
  9. ^ NCBI CIROP Isoform 2 transcript [8]
  10. ^ MyHits Motif Scan tool[9]
  11. ^ GPS sumoylation tool [10]
  12. ^ PSORT II tool [ https://psort.hgc.jp/cgi-bin/runpsort.pl]
  13. ^ Wei Zheng, Chengxin Zhang, Yang Li, Robin Pearce, Eric W. Bell, Yang Zhang. Folding non-homology proteins by coupling deep-learning contact maps with I-TASSER assembly simulations. Cell Reports Methods, 1: 100014 (2021).
  14. ^ Chengxin Zhang, Peter L. Freddolino, and Yang Zhang. COFACTOR: improved protein function prediction by combining structure, sequence and protein-protein interaction information. Nucleic Acids Research, 45: W291-299 (2017).
  15. ^ Jianyi Yang, Yang Zhang. I-TASSER server: new development for protein structure and function predictions, Nucleic Acids Research, 43: W174-W181, 2015.
  16. ^ Genecards RNF225 entry [11]
  17. ^ Genecards MKI67 entry [12]
  18. ^ Genecards ANTXRL entry [13]
  19. ^ MEROP peptidase M8 family description [14]
  20. ^ Human protein atlas CIROP entry [15]
  21. ^ LMLN orthologs [16]
  22. ^ Invadolysin orthologs [17]
  23. ^ MalaCards entry on heterotaxy disorder [18]
  24. ^ Zvenker-Ravi et al.
  25. ^ 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). [19]
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