CLIP4

Protein

CLIP4 protein predicted tertiary structure. Taken from PhyreRisk.[1] CLIP4

| Available structures

PDB| Ortholog search: PDBe RCSB
| List of PDB id codes

2Z0W

Identifiers
Aliases| CLIP4, RSNL2, CAP-Gly domain containing linker protein family member 4
External IDs| MGI: 1919100; HomoloGene: 11662; GeneCards: CLIP4; OMA:CLIP4 - orthologs
| Gene location (Human)

Chr.| Chromosome 2 (human)[2]

Band| 2p23.2| Start| 29,097,705 bp[2]
End| 29,199,777 bp[2]
| Gene location (Mouse)

Chr.| Chromosome 17 (mouse)[3]

Band| 17|17 E1.3| Start| 72,075,468 bp[3]
End| 72,171,268 bp[3]
| RNA expression pattern

Bgee| | Human| Mouse (ortholog)

|

| Top expressed in

* secondary oocyte

* skin of thigh

* Skeletal muscle tissue of biceps brachii

* Skeletal muscle tissue of rectus abdominis

* germinal epithelium

* skin of hip

* gastrocnemius muscle

* sural nerve

* skin of abdomen

* external globus pallidus

| Top expressed in

* seminiferous tubule

* cardiac muscle tissue of left ventricle

* spermatid

* digastric muscle

* soleus muscle

* sternocleidomastoid muscle

* extensor digitorum longus muscle

* skin of external ear

* masseter muscle

* temporal muscle

More reference expression data
BioGPS| | n/a

| Orthologs

Species| Human| Mouse
Entrez| |

79745

78785

Ensembl| |

ENSG00000115295

ENSMUSG00000024059

UniProt| |

Q8N3C7

Q8CI96

RefSeq (mRNA)| |

NM_001287527
NM_001287528
NM_024692

NM_001271483
NM_001271484
NM_030179
NM_175378

RefSeq (protein)| |

NP_001274456
NP_001274457
NP_078968

NP_001258412
NP_001258413
NP_084455
NP_780587

Location (UCSC)| Chr 2: 29.1 – 29.2 Mb| Chr 17: 72.08 – 72.17 Mb
PubMed search| [4]| [5]
Wikidata
| View/Edit Human| View/Edit Mouse

|

CAP-Gly Domain Containing Linker Protein Family Member 4 is a protein that in humans is encoded by the CLIP4 gene.[6] In terms of conserved domains, the CLIP4 gene contains primarily ankyrin repeats and the eponymous CAP-Gly domains.[6] The structure of the CLIP4 protein is largely made up of coil, with alpha helices dominating the rest of the protein.[7] CLIP4 mRNA expression occurs largely in the adrenal cortex and atrioventricular node.[8] The literature encompassing CLIP4's conserved domains and paralogs points toward microtubule regulation as a possible function of CLIP4.

## Gene

[edit]

The human CLIP4 gene, also known as Restin-Like Protein 2 (RSNL2),[9] is located on the plus strand of the short (p) arm of chromosome 2 at region 2, band 3[9] 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.[9]

## Transcript

[edit]

### Transcript variants

[edit]

Transcript  | mRNA size (nucleotides)

|

CLIP4 transcript variant 1[10] | 4299
CLIP4 transcript variant 2[11] | 4295
CLIP4 transcript variant 3[12] | 2353

## Protein

[edit]

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.[9] 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.[7]

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.[13] The molecular weight is about 65 kD.[13] The most abundant amino acid in CLIP4 is Serine, which makes up 10.7% of the protein.[14] 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.[14] 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.[14] 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.[14] 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.[14]

### Protein isoforms

[edit]

Isoform  | Protein size (amino acids)

|

CLIP4 isoform 1[15] | 705
CLIP4 isoform 2[16] | 599

## Expression

[edit]

CLIP4 RNA expression is consistently measured to a high degree in the thyroid.[6] Additionally, high degrees of transcription occur in the adrenal cortex and atrioventricular node.[8] 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.[17] 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.[17]

CLIP4 protein expression seems to be highly expressed during Ada3 deficiency.[18] There also exists a higher trend towards higher CLIP4 expression in the absence of U28.[18]

## Regulation

[edit]

### Gene

[edit]

#### Common transcription factor binding sites

[edit]

These transcription factors were chosen and organized based on proximity to the promoter and matrix similarity.[19]

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

[edit]

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.[20]

### Protein

[edit]

The human CLIP4 protein is localized within the cellular nuclear membrane.[21] CLIP4 does not have a signal peptide due to its intracellular localization.[22] It also does not have N-linked glycosylation sites for that same reason.[23] CLIP4 is not cleaved.[24] However, numerous O-linked glycosylation sites are present.[25] 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.[26]

## Function

[edit]

CAP-Gly domains are often associated with microtubule regulation.[27] In addition, ankyrin repeats are known to mediate protein-protein interactions.[28] Furthermore, CLIP1, a paralog of CLIP4 in humans, is known to bind to microtubules and regulate the microtubule cytoskeleton.[29] The CLIP4 protein is also predicted to interact with various microtubule-associated proteins.[30] As a result, it is likely that the CLIP4 protein, although uncharacterized, is associated with microtubule regulation.

## Interacting Proteins

[edit]

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.[30]

## Clinical significance

[edit]

### Importance in various cancers

[edit]

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.[31] 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.[32] This indicates that CLIP4 could be used for early detection of gastric cancer.[33] A similar finding was also documented for prostate cancer, in which CLIP4 was found to be hypermethylated in patients with prostate cancer.[34]

### Importance in other diseases

[edit]

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).[35] 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.[36]

## Homology

[edit]

### CLIP4 orthologs

[edit]

These orthologs were chosen and organized based on estimated date of divergence from the human protein as well as the global sequence identity.[37]

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

[edit]

1. ^ "PhyreRisk". phyrerisk.bc.ic.ac.uk. Retrieved 2020-05-03.
2. ^ a b c GRCh38: Ensembl release 89: ENSG00000115295 – Ensembl, May 2017
3. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024059 – Ensembl, May 2017
4. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
6. ^ a b c "CLIP4 CAP-Gly domain containing linker protein family member 4 [Homo sapiens (human)] - Gene - NCBI". ncbi.nlm.nih.gov. Retrieved 2020-05-01.
7. ^ a b "CFSSP: Chou & Fasman Secondary Structure Prediction Server". biogem.org. Retrieved 2020-05-03.
8. ^ a b "BioGPS - your Gene Portal System". biogps.org. Retrieved 2020-05-01.
9. ^ a b c d "CLIP4 Gene - GeneCards | CLIP4 Protein | CLIP4 Antibody". genecards.org. Retrieved 2020-05-01.
10. ^ "Homo sapiens CAP-Gly domain containing linker protein family member 4 (CLIP4), transcript variant 1, mRNA". 2020-04-25. `{{cite journal}}`: Cite journal requires `|journal=` (help)
11. ^ "Homo sapiens CAP-Gly domain containing linker protein family member 4 (CLIP4), transcript variant 2, mRNA". 2020-04-25. `{{cite journal}}`: Cite journal requires `|journal=` (help)
12. ^ "Homo sapiens CAP-Gly domain containing linker protein family member 4 (CLIP4), transcript variant 3, mRNA". 2020-04-25. `{{cite journal}}`: Cite journal requires `|journal=` (help)
13. ^ a b "ExPASy - Compute pI/Mw tool". web.expasy.org. Retrieved 2020-05-03.
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18. ^ a b "CLIP4 - GEO Profiles - NCBI". ncbi.nlm.nih.gov. Retrieved 2020-05-01.
19. ^ "Sequence Utilities". bioline.com. Retrieved 2020-05-01.
20. ^ "RNA secondary structure prediction". genebee.msu.su. Archived from the original on 2021-09-17. Retrieved 2020-05-01.
21. ^ "PSORT II Prediction". psort.hgc.jp. Retrieved 2020-05-03.
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27. ^ Weisbrich A, Honnappa S, Jaussi R, Okhrimenko O, Frey D, Jelesarov I, et al. (October 2007). "Structure-function relationship of CAP-Gly domains". Nature Structural & Molecular Biology. 14 (10): 959–67\. doi:10.1038/nsmb1291. PMID 17828277. S2CID 37088265.
28. ^ Li J, Mahajan A, Tsai MD (December 2006). "Ankyrin repeat: a unique motif mediating protein-protein interactions". Biochemistry. 45 (51): 15168–78\. doi:10.1021/bi062188q. PMID 17176038.
29. ^ "UniProtKB - P30622 (CLIP1_HUMAN)". UniProt. Archived from the original on 2010-12-16. Retrieved 3 May 2020.
30. ^ a b "CLIP4 protein (human) - STRING interaction network". string-db.org. Retrieved 2020-05-03.
31. ^ "CLIP4 - CAP-Gly domain-containing linker protein 4 - Homo sapiens (Human) - CLIP4 gene & protein". uniprot.org. Retrieved 2020-05-01.
32. ^ Pirini F, Noazin S, Jahuira-Arias MH, Rodriguez-Torres S, Friess L, Michailidi C, et al. (June 2017). "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\. doi:10.18632/oncotarget.16258. PMC 5503549. PMID 28418867.
33. ^ Pirini F, Noazin S, Jahuira-Arias MH, Rodriguez-Torres S, Friess L, Michailidi C, et al. (June 2017). "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\. doi:10.18632/oncotarget.16258. PMC 5503549. PMID 28418867.
34. ^ Kron K, Pethe V, Briollais L, Sadikovic B, Ozcelik H, Sunderji A, et al. (2009-03-13). "Discovery of novel hypermethylated genes in prostate cancer using genomic CpG island microarrays". PLOS ONE. 4 (3): e4830. Bibcode:2009PLoSO...4.4830K. doi:10.1371/journal.pone.0004830. PMC 2653233. PMID 19283074.
35. ^ Gehrau R, Mas V, Archer K, Maluf D (2012-06-06). "Biomarkers of disease differentiation: HCV recurrence versus acute cellular rejection". Fibrogenesis & Tissue Repair. 5 (Suppl 1): S11. doi:10.1186/1755-1536-5-S1-S11. PMC 3368799. PMID 23259646.
36. ^ "Barbara Dema". Discovery Medicine.
37. ^ "Nucleotide BLAST: Search nucleotide databases using a nucleotide query". blast.ncbi.nlm.nih.gov. Retrieved 2020-05-03.