Single-pass membrane and coiled-coil domain-containing protein 3 is a protein that is encoded in humans by the ''SMCO3'' gene.

Gene

Aliases

''SMCO3'' has 2 aliases, C12orf69 and LOC440087.

Location

''SMCO3'' is located on the negative strand of chromosome 12 (12p12.3) and spans 10,460 base pairs (chr12:14,803,723-14,814,182). It has 2 exons that flank a single intron.

Gene Neighborhood

''SMCO3'' is flanked by WW domain binding protein 11 (WBP11) and Ecto-ADP-ribosyltransferase 4 (ART4) on the minus strand and overlaps with

C12orf60 Uncharacterized protein C12orf60 is a protein that in humans (''Homo sapiens'') is encoded by the ''C12orf60'' gene. The gene is also known as ''LOC144608'' or ''MGC47869''. The protein lacks transmembrane domains and helices, but it is rich in Al ...

on the plus strand. There is only a single isoform of this gene.

Expression

''SMCO3'' is expressed in very low levels in several different human tissues including cervix, connective tissue, eye, lung and prostate. This highest expression of ''SMCO3'' is seen in the kidney, liver and spleen. ''SMCO3'' is also expressed at higher levels in cancers, especially chondrosarcoma and

clear-cell renal cell carcinoma Clear-cell renal-cell carcinoma (CCRCC) is a type of renal-cell carcinoma. Genetics Cytogenetics * Alterations of chromosome 3p segments occurs in 70–90% of CCRCCs * Inactivation of von Hippel–Lindau disease ( VHL) gene by gene mutation a ...

. ''SMCO3'' expression is only seen in the fetus and adult and not in the embryoid bodies,

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 ...

s, infants and juveniles stages of development. The expression of ''SMCO3'' appears to depend upon the species, with the '' Mus musculus'' homolog of ''SMCO3'' expressed at much higher levels in the eye compared to humans.

Promoter

The promoter region of ''SMCO3'' is 1,100 base pairs long and begins 961 base pairs upstream of the 5' UTR with the end of the promoter completely overlapping the first exon.

Variants

There are 2,152 known nucleotide-level variants of which 27 are coding synonymous

single nucleotide polymorphisms In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...

. The vast majority of single nucleotide polymorphisms (SNPs) occur within the intron with only a quarter occurring translated regions. No ''SMCO3'' variants are known to be associated with any disorder.

mRNA

Splice Variants

The

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

transcript of ''SMCO3'' is 2,104 base pair long. There are no mRNA variants of ''SMCO3'.''

Regulation

The SMCO3 promoter has many transcription factors binding sites including for cartilage homeoprotein 1, cAMP-responsive element binding proteins, PAR/bZIP family and vertebrate TATA binding protein factor.

Protein

General Properties

SMCO3 is 225 amino acid long with a predicted molecular weight of 24.9. It is a slightly basic protein with 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 8.3.

Composition

SMCO3 is comparably enriched in

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...

and comparably poor in

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...

and

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...

compared to other human proteins. SMCO3 contains several long, uncharged segments but does not have any significantly charged segments. Despite being a

transmembrane protein A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

there are no significantly hydrophobic regions nor any significantly hydrophilic regions.

Domains and Motifs

SMCO3 has a single domain, DUF4344 (aa15:221) which is currently uncharacterised. C12orf60 also contains this domain. It contains a single transmembrane region (aa155-175) and has two coiled-coil regions (aa62-92, aa183-207). The

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

of SMCO3 contains a KKXX-like motif suggesting

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

localisation. SMCO3 tertiary2

Structure

The secondary structure of SMCO3 consists of several α-helices and a single β-pleated sheet interspersed with disordered coiled coil regions. in Orthologs of SMCO3 similarly show secondary structure dominated by alpha helices. There are no disulfide bridges predicted in the

tertiary structure Protein tertiary structure is the three dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains may int ...

Biochemical Function

The function of the SMCO3 protein is currently unknown.

Post-Translational Modifications

The N-terminus of SMCO3 is cleaved, the first methionine residue removed and the

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

acetylated to improve stability. Additionally there are several sites that are likely phosphorylated and a single

N-linked glycosylation ''N''-linked glycosylation, is the attachment of an oligosaccharide, a carbohydrate consisting of several sugar molecules, sometimes also referred to as glycan, to a nitrogen atom (the amide nitrogen of an asparagine (Asn) residue of a protein), ...

site which is typical in ER integral membrane proteins. Unlike typical ER integral membrane proteins there is no amino-acid signal sequence.

Sub-Cellular Localisation

SMCO3 contains a transmembrane domain (aa155-175). Additionally the KKXX-like motif highly suggest that it is an endoplasmic reticulum integral membrane protein.

Interacting Proteins

Two-hybrid assays have identified that SMCO3 interacts with five proteins: FUS RNA Binding Protein (FUS),

mitogen-activated protein kinase 9 Mitogen-activated protein kinase 9 is an enzyme that in humans is encoded by the ''MAPK9'' gene. Function The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical s ...

(MAPK9), STN1 subunit of CST complex (OBFC1), protein phosphatase 2 catalytic subunit alpha (PPP2CA) and tripartite motif containing 39 (TRIM39). However, it is not known to take part in any pathway although the structure indicates that it takes part in protein-protein interactions. PP2CA, OBFC1, FUS1 and MAPK9 are all either implicated in cancer or have altered expression in cancer which suggests that SMCO3 may be useful as an eQTL for certain cancers.

Clinical Significance

Mutations

Only 3.4% of SNPs were predicted to be deleterious, of which none had any clinical significance.

Disease Associations

GWAS showed no significant associations of ''SMCO3'' with any disease or traits. ''SMCO3'' is not known to be implicated in any disease. ''SMCO3'' is expressed at higher levels in certain cancers, especially chondrosarcoma and

Evolution

Conservation

The amino acid sequence of SMCO3 is highly conserved compared to other human proteins. There is dramatically lower levels of sequence divergence than expected, even compared to proteins known to have low levels of sequence divergence with time.

Homology

SMCO3 in largely conserved in

amniote Amniotes are a clade of tetrapod vertebrates that comprises sauropsids (including all reptiles and birds, and extinct parareptiles and non-avian dinosaurs) and synapsids (including pelycosaurs and therapsids such as mammals). They are disti ...

s. Orthologs have been identified in many mammals, reptiles and birds. The closest ortholog is found in ''

Pan troglodytes The chimpanzee (''Pan troglodytes''), also known as simply the chimp, is a species of Hominidae, great ape native to the forest and savannah of tropical Africa. It has four confirmed subspecies and a fifth proposed subspecies. When its close r ...

'' and has a 99.7% sequence similarity. More distant homologs have also been identified in a select few

bony fish 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 cartilag ...

but orthologs are not seen in

cartilaginous fish Chondrichthyes (; ) is a class that contains the cartilaginous fishes that have skeletons primarily composed of cartilage. They can be contrasted with the Osteichthyes or ''bony fishes'', which have skeletons primarily composed of bone tissue ...

insect Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body ( head, thorax and abdomen), three pairs ...

s or other invertebrates. No paralogs of SMCO3 in humans have been identified. {, class="wikitable sortable mw-collapsible" , + !Species !Common Name !Estimated Time of Divergence (MYA) !NCBI Accession Number !Sequence Length (aa) !Sequence Identity (%) , - , ''Homo sapiens'' , Humans , 0 , XP_016874801.1 , 225 , 100 , - , ''Rhinopithecus roxellana'' , Golden snub nosed monkey , 29.44 , XP_010366768.1 , 225 , 94.7 , - , ''Oryctolagus cuniculus'' , European rabbit , 90 , XP_002712692.1 , 225 , 91.1 , - , ''Delphinapterus leucas'' , Beluga whale , 96 , XP_022433365.1 , 225 , 92.0 , - , ''Phascolarctos cinereus'' , Koala , 159 , XP_020849872.1 , 225 , 80 , - , ''Pygoscelis adeliae'' , Adaliae penguin , 312 , XP_009320673.1 , 225 , 59.6 , - , ''Anolis carolinensis'' , Green anole , 312 , XP_016849216.1 , 227 , 53.8 , - , ''Lepisosteus oculatus'' , Spotted Gar , 435 , XP_015199541.1 , 215 , 39.9

References

Proteins