Coiled-coil domain containing 42B

CCDC42B gene has only one major paralogs CCDC42'(CCDC42A)

Human CCDC42B gene is found in ~58 orthologs species.[5] CCDC42B higher conservation in many mammalian orthologs species compared to non-mammalian orthologs species. Higher conservation of CCDC42B gene in several strict orthologs (mammalian): chimpanzee, rhesus monkey, dog,cow, mouse, rat and chicken, and identities that range between 95%-69%. Lower conservation of CCDC42B gene in distant homologs (non-mammalian): birds, reptile, amphibians and fish and identities that range between 23%-40%. The figure shows comparison between strict orthologs and distant homologs for conservation of CCDC42B (purple color: matched amino acid residues ; blue: conserved residues ; pink: similar residues ; white: different residues )

Strict orthologs vs. Distant Homologs for CCDC42B.

According to Biology Workbench,[9] a phylogenetic tree was constructed showing the divergent of CCDC42B across species.The percent identity vs. the divergent time of orthologs species compared to human sequence is shown below. The figure illustrates the evolutionary history of CCDC42B gene in various species (shown in the orthologs space). The closely related species has higher percent identity, which provides statistical evidence for higher amino acids conservation.Distantly related species to human CCDC42B showed lower percent identity, which supports the few conservation of amino acid residue. The figure highlights the amount of changes occurred in CCDC42B evolution and rate of mutation in the gene.

Divergence of CCDC42B across species.

Human CCDC42B gene contains 9 introns and 8 different mRNA transcripts are produced: 4 alternatively spliced variants and 4 un-spliced variants. Alternative splicing results in encoding 2 very good proteins, 3 good proteins and 3 non-coding proteins.[10]

CCDC42B protein of unknown function contains coiled-coil domain of unknown function (DUF4200) that belongs to Eukaryote family and located at range of 34-159 amino acids. The DUF4200 domain has been conserved in Eukaryote. Coiled coil structure consists of two alpha helices wrapped around each other to form a twist. Heptad repeat pattern (abcdefg)n forms the sequence of coiled coil structure, where a and d are hydrophobic, e and g are polar of charged.

ExPASy Proteomics Tool[13] was primarily used to analyze post-transcriptional modifications of CCDC42B protein. Human CCDC42B N-terminus Acetylation (A2) corresponded in 5 out of 6 orthologs. Drosophila has no Ala, Gly, Ser or Thr at position 1-3, thus N-terminus acetylation is conserved in human CCDC42B. Human CCDC42B protein has conserved SUMOylation site, since lysine (K) at position 285 was conserved in 5 out of 6 orthologs, mostly closely related organisms showed the conservation of lysine. Phosphorylation events occur mostly in CCDC42B, which is suggested to be involved in signaling pathways. Human CCDC42B phosphorylation site of tyrosine at position 8 (Y8) was fully conserved in all 6 orthologs species (the site corresponded with sulfation site). Also other phosphorylation sites in the human CCDC42B protein were conserved in the orthologs (illustrated in the multiple sequence alignment). The same amino acid residues in human CCDC42B protein are subjected to competing phosphorylation and O-linked glycosylation.However, glycosylation sites occur mostly in serine and threonine residues that would be phosphorylated by serine/ threonine kinases. Thus, phosphorylation of the Ser/Thr residues would prevent O-GlcNAc from processing. Human CCDC42B protein has conserved GPI-modification site of Alanine (A) at position 293 that was conserved in 4 out of 6 orthologs.

Post-Transcriptional Modification.

CCDC42B protein form a secondary structure based upon alpha-helices. The structure of CCDC42B is predicted to contain several alpha-helices, and other random coils. Hairpin loop structures were detected at the 5'UTR and 3'UTR region of CCDC42B. Also, leucine zipper domain was found overlapping with coiled-coil domain. The attached image shows comparison between human CCDC42B and 5 other orthologs species which supports that human CCDC42B is primarily composed of alpha helices for its secondary structure.

According to CBLAST,[20] the CCDC42B protein sequence was aligned with 2I1K_A (Chain A, Moesin From Spodoptera Frugiperda Reveals The Coiled-Coil Domain At 3.0 Angstrom Resolution), and an E-value of 1.00e-03 was obtained. The aligned sequences from 164-243 AA for CCDC42B, and 302-381 AA for 2I1K_A resulted in 22% identity between both sequences in 80 amino acid residues.The structure shows only the aligned sequence of CCDC42B with 2I1K_A. Predicted structure (blue: not similar residues, red: conserved residues, gray: not aligned CCDC42B residues with 2I1K_A).

Promoter region for Human CCDC42B showing major Transcription Binding Factors.

According to Genomatix,[22] the Promoter region contains 859 base pairs and it is located on the positive strand of chromosome 12 from region 113,586,906 to 113,587,764 upstream of CCDC42B gene. The promoter region was predicted to contain sites for transcription binding factors that regulate expression of CCDC42B. The Attached image illustrate important transcription binding factors in the promoter region for human CCDC42B .

CCDC42B gene has a narrowed expression in tissues. The gene has higher expression in respiratory epithelia and fallopian tube; Moderate expression in intestine and liver; low to none expression in other normal tissues. Coiled coil domain containing 42B is involved in some types of cancer. CCDC42B gene is expressed in low to moderate level in tumor cell.[21][23][24]

Human CCDC42B is located at chromosome 12 (12q24.13), which is linked to skeletal deformities, hypochondrogenesis, achondrogenesis, and kniest dysplasia. According to OMIM[29] search chromosome 12 (12q24.1) is linked Noonan syndrome 1 that is caused by heterozygote mutation in PTPN11 gene product, SH-PTP2, and primarily causing facial developmental defects and heart defects.

Two SNPs (Y8, Q280) are highly conserved in many orthologs species. Thus, these residues can change function of protein leading to possible disease not only in human.