C2orf16 is a protein that in humans is encoded by the C2orf16 gene. Isoform 2 of this protein (NCBI ID: CAH18189.1 henceforth referred to as C2orf16) is 1,984 amino acids long. The gene contains 1 exon and is located at 2p23.3. Aliases for C2orf16 include Open Reading Frame 16 on Chromosome 2 and P-S-E-R-S-H-H-S Repeats Containing Sequence. 68 orthologs are known for this gene, including in mice and sheep, but no paralogs have been found.

Gene

The C2orf16 isoform 2 is a 6.2 kb, 1 exon gene at locus 2p23.3, and contains P-S-E-R-S-H-H-S repeats on the C-terminal side of the gene from amino acid 1,559 to 1,903. These repeats appear to have arisen from a

transposable element A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transp ...

. Primates show more P-S-E-R-S-H-H-S repeats than other mammalian orthologs do.

Expression

C2orf16 is found to be highly expressed in the

testes A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testoster ...

and a retinoic acid and mitogen-treated

human embryonic stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...

line, but is not known to be expressed differently in age or disease

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

s. C2orf16 is also seen to have high expression in the pre- implantation

embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

from the 4-cell embryo stage to the

blastocyst The blastocyst is a structure formed in the early embryonic development of mammals. It possesses an inner cell mass (ICM) also known as the ''embryoblast'' which subsequently forms the embryo, and an outer layer of trophoblast cells called the t ...

stage. C2orf16 is not seen to have rapamycin sensitive expression. C2orf16 is also seen to significantly increase expression in c-MYC knockdown breast cancer cells.

mRNA

Isoforms

Two

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

exist of C2orf16. Isoform 1 is 5,388 amino acids long encoded in 5

exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

over 16,401

base pairs A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...

. Isoform 2 uses an alternate start site of transcription and is considerably shorter at 1,984 amino acids long encoded in 1 exon over 6,200 base pairs.

Expression Regulation

One miRNA is predicted to bind to the 3'UTR of C2orf16, accession number MI0005564.

Protein

C2orf16 has a predicted

molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

of 224kD and a predicted

isoelectric point The isoelectric point (pI, pH(I), IEP), is the pH at which a molecule carries no net electrical charge or is electrically neutral in the statistical mean. The standard nomenclature to represent the isoelectric point is pH(I). However, pI is also u ...

of 10.08, values that are relatively constant between orthologs. The protein includes higher than average composition of serine, histidine, and arginine and a lower than average composition of alanine.

Compositional Features

A positive charge cluster is found from amino acid residues 1,274 to 1,302. An

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...

rich region is found from amino acids 1,545 to 1,933, a

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

rich region is found from amino acids 1,568 to 1,934, and a

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...

rich region is found from amino acids 1,630 to 1,853. A dot matrix analysis reveals a heavily repeated region from approximately residue 1,500 to 1,984, this being the P-S-E-R-S-H-H-S repeat. a small band of dots at approximately amino acid 1,200 denotes a half repeat of the P-S-E-R-S-H-H-S sequence. Dot Matrix analysis of C2orf16

C2orf16 isoform 2 has no

transmembrane domains A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bil ...

, and is predicted to be localized to the nucleus after translation due to two

nuclear localization sequence A nuclear localization signal ''or'' sequence (NLS) is an amino acid sequence that 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines o ...

s predicted at residues 1,233 and 1,281. No

nuclear export sequence A nuclear export signal (NES) is a short target peptide containing 4 hydrophobic residues in a protein that targets it for export from the cell nucleus to the cytoplasm through the nuclear pore complex using nuclear transport. It has the opposite ...

is conserved amongst orthologs, suggesting C2orf16 is not meant to leave the nucleus after import. No N- or C- terminal modifications were predicted.

Sub-cellular Localization

C2orf16 is predicted to be localized to the nucleus after transcription.

Structure

The 3D structure of C2orf16 is predicted to have three major domains. Domain 1 is from amino acids 1 to 662, domain 2 is from amino acids 674 to 1,487, and domain 3 is from amino acids 1,488 to 1,984. Domain 1 and 2 are predicted to be connected via a stretch of 12 amino acids not otherwise organized into a

secondary structure Protein secondary structure is the three dimensional conformational isomerism, form of ''local segments'' of proteins. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...

allowing flexibility between domains 1 and 2. Domain 2 is predicted to have protein interacting domains for

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

s. Domain 3 is predicted to follow a "balls on a string" structure and has many sites for possible phosphorylation.

Protein Interactions

C2orf16 has been shown to have a physical interaction with

proto-oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

Myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' (MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes referre ...

by tandem affinity purification.

Ortholog Phylogeny

68 orthologs are known for C2orf16. The protein seems to have appeared in the mammalian evolutionary history 320 million years ago, around the divergence of mammals from reptiles. This history would explain why orthologs do not exist in

amphibian Amphibians are tetrapod, four-limbed and ectothermic vertebrates of the Class (biology), class Amphibia. All living amphibians belong to the group Lissamphibia. They inhabit a wide variety of habitats, with most species living within terres ...

reptile Reptiles, as most commonly defined are the animals in the class Reptilia ( ), a paraphyletic grouping comprising all sauropsids except birds. Living reptiles comprise turtles, crocodilians, squamates (lizards and snakes) and rhynchocephalians ( ...

bird Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweigh ...

s, nor other more distantly related species. Any orthologs from species more distant from humans than other mammals are likely not related in function, however, the P-S-E-R-S-H-H-S repeat is present in

bony fishes Osteichthyes (), popularly referred to as the bony fish, is a diverse superclass of fish that have skeletons primarily composed of bone tissue. They can be contrasted with the Chondrichthyes, which have skeletons primarily composed of cartilage ...

crustacean Crustaceans (Crustacea, ) form a large, diverse arthropod taxon which includes such animals as decapods, seed shrimp, branchiopods, fish lice, krill, remipedes, isopods, barnacles, copepods, amphipods and mantis shrimp. The crustacean group ...

s, stramenopiles including potato blight,

plant Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclud ...

ae, and

prokaryote A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Connec ...

s. The transposon repeat may have been reintroduced to mammals by a

viral vector Viral vectors are tools commonly used by molecular biologists to deliver genetic material into cells. This process can be performed inside a living organism (''in vivo'') or in cell culture (''in vitro''). Viruses have evolved specialized molecul ...

Repeat Sequence

The P-S-E-R-S-H-H-S repeat sequence is seen to be conserved in orthologs for C2orf16, and is conserved in organisms as distantly related as oomycete slime mold and plants including the chloroplasts of Ashby's Wattle. The S-P-S-E-R portion of the repeat is seen to be the most important for conservation, as seen by alignment with these orthologs and by creation of a Logo. The conservation analysis of the repeat shows the initial S-P-S is highly conserved, possibly for phosphorylation(S) and structure(P), and the R is almost completely conserved, mutating to a Lysine in some orthologs, implying the positive charge is necessary for the purpose of the repeat. The 3D shape of the repeat sequence is unclear as it has been predicted to be either balls-on-a-string or an antiparallel beta-sheet structure.

Function

C2orf16 isoform 2 is predicted to have a possible function in

mitosis In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...

regulation through its nuclear localization, predicted transcription factor binding site, physical association with

, and increased expression in c-MYC knockdown breast cancer cells.

Clinical Significance

There are four patents on record for C2orf16, one each involving: cancerous PPP2RIA and ARID1A mutations,

Alzheimer's Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...

predisposition, viral vaccine diversity, and copy number variation relation to

common variable immunodeficiency Common variable immunodeficiency (CVID) is an immune disorder characterized by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM and IgA. Symptoms generally include high susceptibility to foreign i ...

. C2orf16 is also shown to have increased expression in some breast cancer lines, as well as being involved with

which is a common oncogene, making C2orf16 a possible oncogene to target in cancer treatments.

References

{{reflist Proteins