CLIP4

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

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

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

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]

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]

References

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