Draft:CAGE-1

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CAGE-1

Cancer Antigen 1 (CAGE-1) is a protein which, in Homo Sapiens (humans), is encoded by the CAGE-1 gene, with a structure containing of mostly alpha helices. CAGE-1 seems to be involved in cancer, when it has a higher expression in the tissue, but is expressed in the testis in healthy tissue . It also has been identified that it does not have any extracellular functions and is localized in the cell nucleus and cytoplasm.

CAGE-1 Tertiary Structure-Whole Protein

Gene

In the human genome, CAGE-1 is located on the minus strand of Chromosome 6 at gene locus p24.3. Figure Cytogenetic Locus of CAGE-1, shows the exact location of where CAGE-1 is located according to NCBI Gene. There are 14 exons (Transcript Variant 1) in the sequence of CAGE-1 and approximately 120,000 base pairs (bp), with the coding sequence only spanning about 3,300 bp.

Cytogenetic Locus of CAGE-1

Aliases: Cancer/Testis Antigen 3 (CT3); Cancer/Testis Antigen 95 (CT95)

Expression

In Homo Sapiens, CAGE-1 is moderately, ubiquitously expressed across tissues with a higher expression at Universal Human Reference RNA and the testis in healthy tissue. Since CAGE-1 is ubiquitously expressed across tissues, this leads to it being relatively more abundant than other proteins. Higher expression can lead to different types of cancers, such as lung or cervical cancer.

mRNA

CAGE-1 is known to have three transcript variants, each with unique distinctions, which are described in Table 1. A 5' Untranslated Region (UTR) and a 3' UTR were both identified in the nucleotide sequence with neither of them having excessive length.

Table 1: Transcript Variants

Transcript Variants	Size (# of bp)	Exon Usage	Distinctions
1	3283	14	Longest Transcript
2	3108	13	Lacks alternate in-frame exon in the central coding region; uses an alternate exon in the 3' coding region and 3' UTR
3	2879	11	Lacks two alternate exons; uses a downstream start codon

Protein

In Homo Sapiens, the Cancer Antigen 1 protein is encoded by the CAGE-1 gene. The predicted average molecular weight of CAGE-1 (isoform 1) in Homo Sapiens is 90 kDa and the isoelectric point (pI) is 5.2. Since the pI is 5.2, this means that the pH is also 5.2 leading CAGE-1 to being more of an acidic protein. CAGE-1 thus contains more acidic residues like glutamic and aspartic acid, as demonstrated in a Compositional Analysis done by SAPS. These results were also consistent among orthologs of the protein, including Mus musculus (mouse) and Gallus gallus (chicken).

Isoforms

CAGE-1 human protein has three different isoforms, as shown in Table 2.

Table 2: Isoforms

Isoforms	Size (# of Amino Acids)	Domain Inclusion	Distinctions	Molecular Weight (kDa)
1	839	Coiled Coil Domain	Longest Isoform	90
2	824	Coiled Coil Domain	Lacks an internal segment; has a longer and distinct C-terminus	95
3	641	Coiled Coil Domain	Lacks an internal segment; shorter N-terminus	75

Sequence Domains/Motifs

CAGE-1 in Homo Sapiens has four sequence motifs, according to Genome Net-Motif Search. The first motif is called CAGE-1 and has two sections that overlap. It is classified as a Cancer-associated gene protein 1 family. The second motif is DUF2209 and is classified as an uncharacterized domain-containing protein conserved in archaea. The third motif is PDZ_4 and is a protein domain that helps regulate cell function and mediates protein-protein interactions. Finally, the fourth motif is DUF1327, which is a domain-containing protein of unknown function. The four motifs and their positions on the CAGE-1 protein can be seen in Figure Four CAGE-1 Protein Motifs Identified.

Four CAGE-1 Protein Motifs Identified

While four motifs were identified, no transmembrane domains are located in CAGE-1, but one intrinsically disordered region has been identified. There are other disordered regions that are predicted, but one has been confidently shown.

Protein Structure

The secondary structure of CAGE-1 consists of Alpha Helices with multiple side chains as seen in Figure CAGE-1 Secondary Structure.

CAGE-1 Secondary Structure

Phyre2 was used to predict the tertiary structure of CAGE-1 with the long chains at the end of the structure showing the disordered regions.

CAGE-1 Tertiary Structure

Subcellular Localization

CAGE-1 protein in Homo Sapiens has a subcellular localization in the cell nucleus and cytoplasm, which means it functions and resides there. It also contains coiled coil domains and a nuclear localization signal, which directs the protein from the cytoplasm to the cell’s nucleus. The nuclear presence of CAGE-1 in cancer cells implies it is involved in regulating the nuclear events associated with tumor progression.

Post-Translational Modifications

CAGE-1 Post-Translational Modifications Schematic

Table 3: Post-Translational Modifications

Tools Used	Investigation	Results
DictyOGlyc	O-(alpha)-GlcNAc glycosylation sites (Serine and Threonine)	Two predicted O-(alpha)-GlcNAc glycosylation sites identified: S190 and S221 exceeded the threshold necessary for glycosylation
NetOGlyc	O-GalNAc (mucin type) glycosylation sites	40 strongly predicted O-GalNAc (mucin type) glycosylation sites and 8 moderately predicted sites - Located throughout the whole sequence
NetPhos	Generic phosphorylation sites	Highest scores seen at S11, S29, S31, S160, S446, S611, S644, T678, S706, S769, S816. (all of these were 99% or greater in likelihood of having a phosphorylation site)
ProP	Arginine and Lysine propeptide cleavage sites	One propeptide cleavage site was predicted at position 813
Sulfinator	Tyrosine Sulfation	One out of eighteen tyrosines predicted to be sulfated tyrosines - Position 5

Conceptual Translation

Depicted on the right is a thumbnail for the conceptual translation of the Homo Sapiens CAGE-1 with annotations to the right-hand side. Things included in the conceptual translation are the 5' Untranslated Region (UTR), the coding sequence, and the 3' UTR. Annotations include Post-Translation Modifications, Start and Stop Codons, Common Variants in CAGE-1, Amino Acids that are conserved, Polyadenylation Sites/Signals and Exon borders

CAGE-1 Conceptual Translation

Protein Interactions

Many proteins have been found to interact with CAGE-1 using methods such as STRING Consortium. Ten proteins were identified to be interacting with CAGE-1 in Homo Sapiens, but only four were of importance and most related to CAGE-1, as seen in Table 4.

Table 4: Protein Interactions

Protein	Function	Basis for Interaction	Localization	Score
RAB11B (Ras-related protein Rab-11B)	Endocytic recycling, regulating apical recycling of several transmembrane proteins	Putative homologs were found interacting in other organisms (score = 0.052) Co-Mentioned in Pubmed Abstracts (score = 0.791)	Cytosol, Golgi, Endosome	0.79
CNDP2 (Cytosolic non-specific dipeptidase)	Hydrolyzes a variety of dipeptides including L-carnosine but has a strong preference for Cys-Gly, functional tumor suppressor in gastric cancer	Co-Mentioned in Pubmed Abstracts (score = 0.791)	Cytosol, Nucleus	0.79
DKKL1 (Dickkopf-like protein 1)	Involved in fertilization by facilitating sperm penetration of the zona pellucida	Co-Expression (score = 0.044) Co-Mentioned in Pubmed Abstracts (score = 0.761)	Cytoplasmic vesicle, Secretory vesicle, Acrosome	0.76
RAB1A (Ras-related protein Rab-1A)	Regulates vesicular protein transport from the endoplasmic reticulum to the Golgi and on to the cell surface	Co-Expression (score = 0.095) Co-Mentioned in Pubmed Abstracts (score = 0.541) Putative homologs were found interacting in other organisms (score = 0.068)	Golgi, Cytosol, Endoplasmic Reticulum	0.58

Evolutionary History

Protein CAGE-1, which is associated with the Cancer Antigen gene family, first appeared approximately 352 million years ago, which was when amphibians first came around. CAGE-1 was not found in fish, invertebrates, fungi, and plants, and its earliest ancestor is primates.

Paralogs

There are no known paralogs of CAGE-1.

Orthologs

CAGE-1 is highly conserved in Homo Sapiens. It can also be found in mammals, reptiles, birds, and amphibians. Table 5 below identifies eighteen orthologs, including humans, to demonstrate how CAGE-1's protein sequence has changed overtime compared to humans.

Table 5: Orthologs

Taxonomic Group	Genus and Species	Common Name	Date of Divergence (MYA)	Accession Number	Sequence Length (aa)	Sequence Identity (%)	Sequence Similarity (%)
Primate	Homo Sapiens	Human	0	NP_001164163.1	839	100	100
	Pongo Abelii	Sumatran Orangutan	15.2	XP_054413145.2	905	96	100
Non-Ape Primate	Carlito Syrichta	Philippine Tarsier	69	XP_021566266.1	769	69	95
	Lemur Catta	Ring-Tailed Lemur	74	XP_045407681.1	794	66	97
Marsupiels	Phascolarctos Cinereus	Koala	160	XP_020865532.1	904	51	55
	Monodelphis Domestica	Gray Short-Tailed Opossum	160	XP_007488051.2	998	51	73
	Notamacropus Eugenii	Tammar Wallby	160	XP_072459852.1	899	50	72
	Antechinus Flavipes	Yellow-Footed Antechinus	160	XP_051826685.1	963	49	72
Monotremes	Tachyglossus Aculeatus	Australian Echidna	180	XP_038626118.1	431	40	48
Birds	Apteryx Rowi	Okarito Brown Kiwi	319	XP_025928647.1	542	37	58
	Rhea Pennata	Darwin's Rhea	319	XP_062424047.1	722	37	34
Reptiles	Mauremys Mutica	Yellowpond Turtle	319	XP_044861538.1	1052	42	64
	Dermochelys Coriacea	Leatherback Sea Turtle	319	XP_043364284.1	786	41	64
	Mauremys Reevesii	Reeves's Turtle	319	XP_039380245.1	1102	41	64
	Chelonia Mydas	Green Sea Turtle	319	XP_043396081.1	1098	41	64
Amphibians	Rhinatrema Bivittatum	Two-Lined Caecilian	352	XP_029446479.1	437	46	11
	Geotrypetes Seraphini	Gabon Caecillian	352	XP_033790611.1	446	46	9
	Microaecilia Unicolor	Tiny Cayenne Caecilian	352	XP_030064763.1	441	45	10

CAGE-1 in Homo Sapiens is a quickly evolving protein as seen in the Figure CAGE-1 Corrected sequence divergence vs. Median Date of Divergence. It evolves around the same rate as Fibrinogen Alpha Chain, which is known to evolve at a very fast pace.

CAGE-1 Corrected sequence divergence vs. Median Date of Divergence

Clinical Significance

CAGE-1 has been researched to show that it is involved in the progression of tumorigenesis, which is the process of normal cells turning into cancer cells. This has been identified by cancer tissues being compared to surrounding mucosa tissues and CAGE-1 having a higher expression in tissues that have cancer. The cancers that are known to consistently have a higher expression of CAGE-1 are cervical, lung, gastric, lung, hepatic, and melanoma. Other cancers have shown CAGE-1 expression, but not as consistently. CAGE-1 continues to show signs of being involved in the progression of cancer, while also being expressed in healthy tissue of the testis.