Biology:CLIP4

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Short description: Protein
CLIP4 protein predicted tertiary structure. Taken from PhyreRisk.[1]
A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

CAP-Gly Domain Containing Linker Protein Family Member 4 is a protein that in humans is encoded by the CLIP4 gene.[2] In terms of conserved domains, the CLIP4 gene contains primarily ankyrin repeats and the eponymous CAP-Gly domains.[2] The structure of the CLIP4 protein is largely made up of coil, with alpha helices dominating the rest of the protein.[3] CLIP4 mRNA expression occurs largely in the adrenal cortex and atrioventricular node.[4] The literature encompassing CLIP4's conserved domains and paralogs points toward microtubule regulation as a possible function of CLIP4.

Gene

The human CLIP4 gene, also known as Restin-Like Protein 2 (RSNL2),[5] is located on the plus strand of the short (p) arm of chromosome 2 at region 2, band 3[5] from base pair 29,096,676 to base pair 29,189,643. CLIP4 is 92,968 base pairs in length and consists of 23 exons.[5]

Transcript

Transcript variants

Transcript mRNA size (nucleotides)
CLIP4 transcript variant 1[6] 4299
CLIP4 transcript variant 2[7] 4295
CLIP4 transcript variant 3[8] 2353

Protein

The human CLIP4 protein is 705 amino acids in length and is composed of two main types of conserved domains: Two CAP-Gly domains and numerous ankyrin repeats.[5] The secondary structure of CLIP4 consists largely of random coil, with alpha helices as the second-most abundant structure and beta sheets as the third-most abundant structure.[3]

The isoelectronic point of the unprocessed CLIP4 protein is slightly basic (8.62 pI), meaning there is a slight excess of basic amino acids compared to acidic amino acids.[9] The molecular weight is about 65 kD.[9] The most abundant amino acid in CLIP4 is Serine, which makes up 10.7% of the protein.[10] Aligned matching blocks of separated, tandem, and periodic repeats are found between positions 340-345 and 542-547, as well as 447-547 and 564-568.[10] The unusual 9-figure periodic element of a singular Lysine followed by eight other amino acids occurs five times within the protein when compared to the swp23s.q dataset.[10] Another unusual phenomenon is a 7-figure periodic element of a negatively charged amino acid followed by six other hydrophobic amino acids, which occurs six times within the protein when compared to the swp23s.q dataset.[10] There are two instances of Serine spacing and two instances of Phenylalanine spacing that comprise unusually large distances when compared to the swp23s.q dataset.[10]

Protein isoforms

Isoform Protein size (amino acids)
CLIP4 isoform 1[11] 705
CLIP4 isoform 2[12] 599

Expression

CLIP4 RNA expression is consistently measured to a high degree in the thyroid.[2] Additionally, high degrees of transcription occur in the adrenal cortex and atrioventricular node.[4] The Human Protein Atlas points toward high RNA expression values in the muscle tissues, as well as some in the skin, endocrine tissues, and proximal digestive tract.[13] Greatest protein expression values appeared in the muscle tissues as well, in addition to some in the lung, gastrointestinal tract, liver & gallbladder, and bone marrow & lymphoid tissues.[13]

CLIP4 protein expression seems to be highly expressed during Ada3 deficiency.[14] There also exists a higher trend towards higher CLIP4 expression in the absence of U28.[14]

Regulation

Gene

Common transcription factor binding sites

These transcription factors were chosen and organized based on proximity to the promoter and matrix similarity.[15]

Transcription Factor Detailed Matrix Info Anchor Base Matrix Similarity Sequence
NOLF Early B-cell factor 1


17
 0.98 taagagTCCCcagggcagaaaca


PAX2 Zebrafish PAX2 paired domain protein


18 0.8 aagagtccccagggcagAAACaa


AP2F Transcription factor AP-2, alpha


16 0.98 ctgcCCTGgggactc


AP2F Transcription factor AP-2, beta


16 0.899 gagTCCCcagggcag


SORY SRY (sex-determining region Y) box 9, dimeric binding sites


35 0.768 aAACAaaatccagtgagggagag


HNF6 CUT-homeodomain transcription factor Onecut-2


32 0.827 aaacaaAATCcagtgag


PAX5 B-cell-specific activator protein


40 0.815 acaaaaTCCAgtgagggagagatgcaggg


ZF16 PR/SET domain 15


36 0.852 aaatccagtgaGGGA


SORY HMGI(Y) high-mobility-group protein I (Y), architectural transcription factor organizing the framework of a nuclear protein-DNA transcriptional complex


78 0.945 tggaAATTttctaccttaggagc


NFAT Nuclear factor of activated T-cells 5


83 0.955 ttttGGAAattttctacct


NFAT Nuclear factor of activated T-cells 5


83 0.871 aggtAGAAaatttccaaaa


CEBP CCAAT/enhancer binding protein (C/EBP), epsilon


89 0.975 agccttttGGAAatt


CAAT Cellular and viral CCAAT box


110 0.91 gcagCCATttaatct


CAAT Avian C-type LTR CCAAT box            


165 0.875 cccaCCAAgcagtgg


CEBP CCAAT/enhancer binding protein (C/EBP), gamma


650 0.866 ctaaTTGCtcaacgt


CEBP CCAAT/enhancer binding protein alpha


651 0.971 cacgttgaGCAAtta


VTBP Mammalian C-type LTR TATA box


680 0.903 tgctgTAAAaggcctaa


TF2B Transcription factor II B (TFIIB) recognition element


983 1 ccgCGCC


TF2B Transcription factor II B (TFIIB) recognition element


1157 1 ccgCGCC


TF2B Transcription factor II B (TFIIB) recognition element


1228 1 ccgCGCC


Transcriptional

The human CLIP4 mRNA sequence has 12 stem-loop structures in its 5' UTR and 13 stem-loop structures in its 3' UTR. Of those secondary structures, there are 12 conserved stem-loop secondary structures in the 5'UTR as well as 1 conserved stem-loop secondary structure in the 3' UTR.[16]

Protein

The human CLIP4 protein is localized within the cellular nuclear membrane.[17] CLIP4 does not have a signal peptide due to its intracellular localization.[18] It also does not have N-linked glycosylation sites for that same reason.[19] CLIP4 is not cleaved.[20] However, numerous O-linked glycosylation sites are present.[21] A high density of phosphorylation sites are present in the 400-599 amino acid positions on the CLIP4 protein, although many are also present throughout the rest of the protein.[22]

Function

CAP-Gly domains are often associated with microtubule regulation.[23] In addition, ankyrin repeats are known to mediate protein-protein interactions.[24] Furthermore, CLIP1, a paralog of CLIP4 in humans, is known to bind to microtubules and regulate the microtubule cytoskeleton.[25] The CLIP4 protein is also predicted to interact with various microtubule-associated proteins.[26] As a result, it is likely that the CLIP4 protein, although uncharacterized, is associated with microtubule regulation.

Interacting Proteins

The CLIP4 protein is predicted to interact with many proteins associated with microtubules; namely, MAPRE1, MAPRE2, and MAPRE3. It is also predicted to interact with CKAP5 and DCTN1, a cytoskeleton-associated protein and dynactin-associated protein respectively.[26]

Clinical significance

Importance in various cancers

CLIP4 activity is correlated with the spread of renal cell carcinomas (RCCs) within the host and could therefore be a potential biomarker for RCC metastasis in cancer patients.[27] Additionally, measurement of promotor methylation levels of CLIP4 using a Global Methylation DNA Index reveals that higher methylation of CLIP4 is associated with an increase in severity of gastritis to possibly gastric cancer.[28] This indicates that CLIP4 could be used for early detection of gastric cancer.[29] A similar finding was also documented for prostate cancer, in which CLIP4 was found to be hypermethylated in patients with prostate cancer.[30]

Importance in other diseases

The presence of CLIP4 was found to be highly increased in samples with predicted severe fibrosis as a result of Chronic Hepatitis C virus (HCV).[31] Additionally, the presence of CLIP4 as a novel self-antigen in Systemic Lupus Arythematosus points to it having a potential role in the disease mechanism.[32]

Homology

CLIP4 orthologs

These orthologs were chosen and organized based on estimated date of divergence from the human protein as well as the global sequence identity.[33]

Binomial Nomenclature Common Name Taxonomic Group Estimated DoD from Human (MYA) Accession Number Sequence Length (AA) Global Sequence Identity to Human Protein (%) Global Sequence Similarity to Human Protein (%)
Homo sapiens (Hsa) Human Primate 0 AAP97312 601 100 100
Aotus nancymaae (Ana) Ma's night monkey Primate 43.2 XP_012330895 704 83.5 83.7
Sorex araneus (Sar) Common shrew Eulipotyphla 96 XP_004620056 707 74 78.5
Antrostomus carolinensis (Aca) Chuck-will's-widow Aves 312 XP_028942997 702 66.5 75.4
Gekko japonicus (Gja) Schlegel's Japanese gecko Reptilia 312 XP_015270366 702 63.8 73.1
Rhinatrema bivittatum (Rbi) Two-lined caecilian Amphibians 351.8 XP_029448862 707 59.5 70.5
Callorhinchus milii (Cmi) Elephant shark Chondrichthyes 473 XP_007895016 715 52.5 65.6
Branchiostoma floridae (Bfl) Florida lancelet Leptocardii 684 XP_002606824 481 40.4 52.8
Saccoglossus kowalevskii (Sko) Acorn worm Enteropneusta 684 XP_006822686 648 35.7 47.5
Ixodes scapularis (Isc) Black-legged tick Arachnid 797 XP_029831090 527 38.9 53
Limulus polyphemus (Lpo) Atlantic horseshoe crab Arachnid 797 XP_013786376 462 38 51.6
Lottia gigantea (Lgi) Owl limpet   Gastropods 797 XP_009046843 669 36.3 49.3
Mizuhopecten yessoensis (Mye) Yesso scallop Bivalvia 797 XP_021359747 633 35.4 47.2
Parasteatoda tepidariorum (Pte) Common house spider Arachnid 797 XP_015914966 616 34.7 47.6
Aplysia californica (Aca) California sea hare Gastropods 797 XP_012945346 653 33.7 45.7
Crassostrea virginica (Cvi) Eastern oyster Bivalvia 797 XP_022315879 646 32.7 45.1
Tetranychus urticae (Tur) Two-spotted spider mite Arachnid 797 XP_015790536 652 31.9 43.5
Centruroides sculpturatus (Csc) Bark scorpion Arachnid 797 XP_023229484 605 30.6 43.4
Penaeus vannamei (Pva) Pacific white shrimp Malacostracans 797 XP_027206746 681 22.9 34
Monosiga brevicollis (Mbr) Choanoflagellate Choanoflagellatea 1023 XP_001748580 576 25.3 40.8

References

  1. ↑ "PhyreRisk". http://phyrerisk.bc.ic.ac.uk/. 
  2. ↑ 2.0 2.1 2.2 "CLIP4 CAP-Gly domain containing linker protein family member 4 [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/79745. 
  3. ↑ 3.0 3.1 "CFSSP: Chou & Fasman Secondary Structure Prediction Server". http://www.biogem.org/tool/chou-fasman/index.php. 
  4. ↑ 4.0 4.1 "BioGPS - your Gene Portal System". http://biogps.org/#goto=genereport&id=79745. 
  5. ↑ 5.0 5.1 5.2 5.3 "CLIP4 Gene - GeneCards | CLIP4 Protein | CLIP4 Antibody". https://www.genecards.org/cgi-bin/carddisp.pl?gene=CLIP4. 
  6. ↑ (in en-US) Homo sapiens CAP-Gly domain containing linker protein family member 4 (CLIP4), transcript variant 1, mRNA. 2020-04-25. http://www.ncbi.nlm.nih.gov/nuccore/NM_024692.6. 
  7. ↑ (in en-US) Homo sapiens CAP-Gly domain containing linker protein family member 4 (CLIP4), transcript variant 2, mRNA. 2020-04-25. http://www.ncbi.nlm.nih.gov/nuccore/NM_001287527.2. 
  8. ↑ (in en-US) Homo sapiens CAP-Gly domain containing linker protein family member 4 (CLIP4), transcript variant 3, mRNA. 2020-04-25. http://www.ncbi.nlm.nih.gov/nuccore/NM_001287528.1. 
  9. ↑ 9.0 9.1 "ExPASy - Compute pI/Mw tool". https://web.expasy.org/compute_pi/. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 "SAPS < Sequence Statistics < EMBL-EBI". https://www.ebi.ac.uk/Tools/seqstats/saps/. 
  11. ↑ "CAP-Gly domain-containing linker protein 4 isoform 1 [Homo sapiens - Protein - NCBI"]. https://www.ncbi.nlm.nih.gov/protein/NP_001274456.1. 
  12. ↑ "CAP-Gly domain-containing linker protein 4 isoform 2 [Homo sapiens - Protein - NCBI"]. https://www.ncbi.nlm.nih.gov/protein/NP_001274457.1. 
  13. ↑ 13.0 13.1 "CLIP4 protein expression summary - The Human Protein Atlas". https://www.proteinatlas.org/ENSG00000115295-CLIP4. 
  14. ↑ 14.0 14.1 "CLIP4 - GEO Profiles - NCBI". https://www.ncbi.nlm.nih.gov/geoprofiles/?term=CLIP4. 
  15. ↑ "Sequence Utilities". https://www.bioline.com/media/calculator/01_12.html. 
  16. ↑ "RNA secondary structure prediction". http://www.genebee.msu.su/services/rna2_reduced.html. 
  17. ↑ "PSORT II Prediction". https://psort.hgc.jp/form2.html. 
  18. ↑ "SignalP-5.0". http://www.cbs.dtu.dk/services/SignalP/. 
  19. ↑ "NetNGlyc 1.0 Server". http://www.cbs.dtu.dk/services/NetNGlyc/. 
  20. ↑ "ProP 1.0 Server". http://www.cbs.dtu.dk/services/ProP/. 
  21. ↑ "NetOGlyc 4.0 Server" (in en). http://www.cbs.dtu.dk/services/NetOGlyc/. 
  22. ↑ "NetPhos 3.1 Server". http://www.cbs.dtu.dk/services/NetPhos/. 
  23. ↑ "Structure-function relationship of CAP-Gly domains". Nature Structural & Molecular Biology 14 (10): 959–67. October 2007. doi:10.1038/nsmb1291. PMID 17828277. https://www.nature.com/articles/nsmb1291. 
  24. ↑ "Ankyrin repeat: a unique motif mediating protein-protein interactions". Biochemistry 45 (51): 15168–78. December 2006. doi:10.1021/bi062188q. PMID 17176038. 
  25. ↑ "UniProtKB - P30622 (CLIP1_HUMAN)". https://www.uniprot.org/uniprot/P30622. 
  26. ↑ 26.0 26.1 "CLIP4 protein (human) - STRING interaction network". https://string-db.org/cgi/network.pl?taskId=4usn7zuMc06t. 
  27. ↑ "CLIP4 - CAP-Gly domain-containing linker protein 4 - Homo sapiens (Human) - CLIP4 gene & protein". https://www.uniprot.org/uniprot/Q8N3C7. 
  28. ↑ "Early detection of gastric cancer using global, genome-wide and IRF4, ELMO1, CLIP4 and MSC DNA methylation in endoscopic biopsies". Oncotarget 8 (24): 38501–38516. June 2017. doi:10.18632/oncotarget.16258. PMID 28418867. 
  29. ↑ "Early detection of gastric cancer using global, genome-wide and IRF4, ELMO1, CLIP4 and MSC DNA methylation in endoscopic biopsies". Oncotarget 8 (24): 38501–38516. June 2017. doi:10.18632/oncotarget.16258. PMID 28418867. 
  30. ↑ "Discovery of novel hypermethylated genes in prostate cancer using genomic CpG island microarrays". PLOS ONE 4 (3): e4830. 2009-03-13. doi:10.1371/journal.pone.0004830. PMID 19283074. Bibcode: 2009PLoSO...4.4830K. 
  31. ↑ "Biomarkers of disease differentiation: HCV recurrence versus acute cellular rejection". Fibrogenesis & Tissue Repair 5 (Suppl 1): S11. 2012-06-06. doi:10.1186/1755-1536-5-S1-S11. PMID 23259646. 
  32. ↑ "Barbara Dema" (in en). Discovery Medicine. http://www.discoverymedicine.com/Barbara-Dema/2014/05/22/advances-in-mechanismsof-systemic-lupus-erythematosus/. 
  33. ↑ "Nucleotide BLAST: Search nucleotide databases using a nucleotide query". https://blast.ncbi.nlm.nih.gov/Blast.cgi?PAGE_TYPE=BlastSearch. 



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