MIPOL1

MIPOL1 , also known as CCDC193 , is a protein that in humans is encoded by the MIPOL1 gene. Mutation of this gene is associated with mirror-image polydactyly in humans, which is a rare genetic condition characterized by mirror-image duplication of digits.

Gene

MIPOL1 is also known as CCDC193.

Locus

The MIPOL1 gene is located at 14q13.3-q21.1 on the plus strand, spanning base pairs 37,197,888 to 37,579,207, consisting of 15 exons and 11 introns. Some notable genes in its neighborhood include SLC25A21 and FOXA1.

mRNA

MIPOL1 has at least 15 known splice isoforms produced by alternative splicing.

Protein

Properties

The unmodified MIPOL1 protein isoform 1 in humans has an isoelectric point of 5.6 and molecular weight 51.5 kDa. Relative to other human proteins, MIPOL1 consists of unusually low amounts of Proline and Glycine and higher amounts of Glutamic acid and Glutamine.

Isoforms

There are at least three known isoforms of this protein in humans produced by alternative splicing: isoform 1, of length 442 amino acids, isoform 2 of length 261 amino acids and isoform 3 of length 169 amino acids.

Domains and motifs

MIPOL1 contains two coiled-coil domains in its C-terminus at positions 107 – 212 and 253 – 435. A bipartite nuclear localization signal is predicted at position 128 – 143.

Post-translational modifications

The following post-translational modifications are predicted using bioinformatics tools for MIPOL1. Multiple phosphorylation sites are predicted for this protein, that are conserved in close orthologs, including a Casein kinase 1 site, three Casein kinase 2 sites, and three NEK2 sites.

Post-translational modification	Amino acid site	Prediction tool
Phosphorylation	Ser, Thr, Tyr	MyHits, NetPhos
O-linked glycosylation	Ser, Thr	NetOGlyc
O-GlcNAcylation	Thr	YinOYang
Glycation	Lys	NetGlycate
SUMOylation	Lys	GPS-SUMO
Ubiquitination	Lys	BDM-PUB

Structure

The exact structure of the MIPOL1 has not yet been characterized. Homology-based and de novo predictions of its tertiary structure suggest that it may consist of inter-twined alpha helices, forming coiled-coil domains.

Sub-cellular localization

Immunofluorescence imaging in the human shows localization in the cytosol. Immunohistochemistry imaging of human prostate tissue also suggests cytosolic localization. A bipartite nuclear localization signal is predicted at position 128 – 143, which is highly conserved in mammalian orthologs, indicating possible localization in the nucleus.

Gene regulation

The predicted promoter sequence for this gene spans from base pair 37196852 to 37198126 and has multiple predicted binding sites for transcription factors such as [GATA Transcription (biology)|transcription factor|GATA binding factors], SMAD3, TP63 and NRF1.

Gene Expression

MIPOL1 is ubiquitously expressed at low levels in humans, with highest expression in the prostate.

Transcript regulation

The RNA secondary structure is stabilized by multiple stem loops that have been predicted, and conserved across closely related species. Multiple binding targets are found for microRNAs such as MIR3163 and MIR190a, that could silence these regions on the mRNA and inhibit translation.

Clinical significance

The MIPOL1 gene is an autosomal dominant gene. It is one of six genes in humans causing non-syndromic polydactyly. Mutation of this gene is associated with mirror-image polydactyly in humans, which is a rare genetic condition characterized by mirror-image duplication of digits in hands and feet.
This gene has also been associated with central nervous system development, and the loss of this gene can cause craniofacial defects and agenesis of the corpus callosum.
The gene is shown to function as a tumor suppressor in nasopharyngeal carcinoma, through the up-regulation of the p21 and p27 pathways. Another study investigating the role of MIPOL1 gene in cancer progression reported that MIPOL1 was downregulated in NPC tumor tissues, and that artificially re-expressing the gene caused tumor suppression by down-regulating angiogenic factors and reducing the phosphorylation of metastasis associated proteins like AKT, p65 and FAK14. MIPOL1 interacts with another well-known tumor-suppressing gene, RhoB and this interaction was confirmed to enhance RhoB activity.
In a study of pediatric high grade glioma, MIPOL1 gene was found to be down-regulated 2.4-fold in the high vascularity tumors
The protein is known to interact with Replicase polyprotein 1ab in SARS-CoV2, which is a protein involved in the transcription and replication of viral RNAs.

Interacting proteins

This protein is known to interact with multiple human proteins, verified via two-hybrid screening. A few notable examples include:
LATS2: Negatively regulates YAP1 in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting cell proliferation and promoting apoptosis.
ZGPAT : A transcription repressor that negatively regulates expression of EGFR, a gene involved in cell proliferation, survival and migration, suggesting that it may act as a tumor suppressor.
RCOR3 : A protein that may act as a component of a co-repressor complex that represses transcription
It also interacts with viral proteins such as:
Replicase polyprotein 1ab : A multifunctional protein involved in the transcription and replication of viral RNAs.
Protein E7 : Plays a role in viral genome replication by driving entry of quiescent cells into the cell cycle.

Origin and evolution

The earliest known ortholog of this protein appeared around 948 million years ago in Trichoplax adhaerens in phylum Placozoa in kingdom Animalia. The next most distant orthologs appear in phylum Cnidaria, around 824 million years ago.

Sequence Homology

The MIPOL1 protein has no known paralogs in humans and other species for which orthologs have been found, therefore, it is the only member of its gene family.
There are more than 300 known orthologs of the MIPOL1 protein in Animalia, ranging from primates to corals and sea anemones in phylum Cnidaria. Orthologs of the protein were found in species as distant as Trichoplax adhaerens, a simple primitive invertebrate species. Table 2 shows a sample of the ortholog space.
Closely related orthologs are found in chordates such as mammals, reptiles, birds and amphibians, with sequence similarities greater than 70%. Sequence lengths of orthologs were similar to the human MIPOL1 protein, with no significant gene duplication observed.
Organisms with sequence similarities in the 55-70% range were found in bony fish, cartilaginous fish and coelacanths. Sequence length is generally longer in these species, with a longer amino acid sequence in the N-terminus.
Distantly related orthologs with similarities less than 50% are found in hemichordates, echinoderms, arthropods, molluscs, cnidaria and placozoa. Multiple sequence alignment with distant orthologs indicates poor alignment in the N-terminus of the protein.
Two COG domains were found in this protein : COG1196 at position 106 - 340 and COG4372 at 259 - 431

Species	Organism Common Name	NCBI Accession	Date of Divergence from humans	Sequence length	Sequence identity to human protein
Homo sapiens	Human		0	442	100
Macaca fascicularis	Crab-eating macaque		29.44	442	94.3
Lipotes vexillifer	Yangtze River dolphin		96	442	85.5
Manis javanica	Malayan pangolin		96	407	77.6
Myotis brandtii	Brandt's bat		96	463	74.6
Chelonia mydas	Green sea turtle		312	440	67.9
Notechis scutatus	Mainland tiger snake		312	429	54.0
Gallus gallus	Chicken		312	429	55.9
Rhinatrema bivittatum	Two-lined caecilian		351.8	443	59.3
Latimeria chalumnae	West Indian Ocean coelacanth		413	532	51.9
Danio rerio	Zebrafish		435	381	38.8
Oryzias melastigma	Indian medaka		435	404	30.9
Amblyraja radiata	Thorny skate		473	497	45.8
Saccoglossus kowalevskii	Acorn worm		684	666	23.3
Asterias rubens	Common starfish		684	646	22.2
Limulus polyphemus	Atlantic horseshoe crab		797	579	19.2
Pecten maximus	Great scallop		797	598	22.5
Exaiptasia pallida	Brown anemone		824	468	27.5
Orbicella faveolata	Mountainous star coral		824	453	27.5
Trichoplax adhaerens	Trichoplax		948	553	22.9

Phylogenetics

Using a linear regression analysis on a plot of corrected percent divergence as a function of date of divergence from humans for different MIPOL1 orthologs, it is estimated that a 1% change in amino acids in the MIPOL1 protein takes 5.68 million years. MIPOL1 protein is evolving at a moderate rate relative to fast evolving protein such as fibrinogen alpha, and slow evolving proteins such as cytochrome C.