C15orf54 (Chromosome 15 Open Reading Frame 54) is a protein in humans that is encoded by the C6orf54 gene. This gene is mostly conserved in mammals, primarily primates. While the function of the gene is currently unknown, the gene has shown high expression in the prostate, thymus, appendix, bone marrow, and lungs.[3]
Gene
C15orf54 is located on chromosome 15 from 39542870 to 39547048 on the direct strand. This gene is 4,180 bases in length. The gene is otherwise known as LOC400360 or FLJ39531. The gene contains 2 distinct gt-ag introns and two exons with two alternatively spliced mRNAs, both encoding the same protein.[3] The NCBI accession number is NC_000015.10.[4]
Location of C15orf54 on chromosome 15
mRNA
Isoforms
C15orf54 has a total of 2 isoforms: variant 1 and variant 2. Variant 1 represents the longer transcript and variant 2 uses an alternate splice site in the 3' exon compared to variant 1.[3]
Variant 1
The complete mRNA is 3095 bp long and contains 2 exons. The 5' UTR contains 383 bp with an in frame stop 48 bp before the Met. The 3' UTR contains 2160 bp followed by the polyA. The standard AATAAA polyadenylation signal is seen about 23 bp before the polyA. The predicted protein product has 183 aa.[3]
Protein
General properties
The sequence for the C15orf54 protein is as follows:[3]
The dominant protein product is 183 amino acids long and has a predicted molecular weight of 21 kDa. The isoelectric point is 9.87.[3] C15orf54 has a relatively high frequency of leucine at 12.0% and a relatively low frequency of tyrosine at 1.1%.[5] The number of multiplets in this sequence is 12. There are no unusual spacings in this protein.[5]
Domains and Motifs
Analysis of C15orf54 showed a globular domain with multiple motif functional sites. One site is the MAPK-docking motif, which consists of one or more basic and two to four hydrophobic residues in adjacent groups. These motifs regulate specific interactions in the MAPK cascade. Another such site is the LIR motif which is a part of the Atg8 protein family ligands and plays a role in selective autophagy by recruiting specific adaptors bound to ubiquitylated proteins, organelles, or pathogens for degradation.[6]
Post-translational modification
C15orf54 is non-myristoylated. There was also no sulfinated sites found in this protein. One motif with a high probability of post translational modification sumoylation sites were found. Sumoylation sites are involved in nuclear-cytosolic transport, transcriptional regulation and protein stability.[7]
Secondary structure
C15orf54 is composed of both alpha helices and beta sheets, as well as turns and some coils. Alpha helices constituted the majority of the protein.[8]
Sub-cellular Localization
The membrane topology was determined to be type 1b with a cytoplasmic tail from 34 to 183, indicating that the C-terminal side will be inside. There was a transmembrane region located from 34 to 50. There were dileucine motifs found in the tail at 39 and 118.[9]
Interacting Proteins
Two interacting proteins were found, lsd2_drome and npfr_drome. Lsd2_drome is a lipid storage droplet surface binding protein and npfr_drome is a neuropeptide F receptor.
Regulation
Gene regulation
Promoter
C15orf54 has one predicted promoter sequence. GXP_6084 is located from 39249718 to 39250757 on the plus strand of chromosome 15 and is composed of 1040 bp.[10]
Transcription factor binding sites
The following table displays the transcription factors most likely to bind to the GXP_6084 promoter for C15orf54.[10]
Matrix Family
Detailed Family Information
TALE
TG-interacting factor belonging to TALE class of homeodomain factors
CART
Binding site for S8 type homeodomains
HAND
T-cell acute lymphocytic leukemia 1, SCL
ZFHX
AREB6 (Atp1a1 regulatory element binding factor 6)
TZAP
Zinc finger and BTB domain containing 48
SAL4
Spalt like 4, DRRS, HSAL4, ZNF797
TEAF
TEA domain family member 4, TEF-3
RUSH
SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 3
EGRF
Wilms Tumor Suppressor
Expression pattern
The gene has shown high expression in the prostate, thymus, appendix, bone marrow, and lungs. NCBI AceView shows that the gene is moderately expressed.[3]
Diagram depicting the expression of C15orf54 in tissues throughout the body.[4]
Transcription regulation
miRNA targeting
TargetScan showed that miRNA hsa-miR-375 was highly conserved across various organisms. This miRNA is specifically expressed in the pancreatic islets, brain, and spinal cord. This miRNA has also been shown to be associated with different cancers, including breast and gastric cancer.[11]
Homology
Rate of evolution
Relative mutation rate of C15orf54 (blue) compared to fibrinogen alpha (grey) and cytochrome C (orange)
Paralogs
No paralogs of C15orf54 have been detected in the human genome.
Orthologs
Orthologs were primarily found in primates, although many different mammals also exhibited sizeable sequence similarity to the human C15orf54 sequence. Below is a table of selected orthologs sorted by date of divergence for the C15orf54 gene, including closely and distantly related orthologs.[12][13] C15orf54 was shown to evolve relatively quickly and evenly over time with a faster rate than both Cytochrome C and Fibrinogen Alpha.
Genus and species
Common Name
Taxonomic Group
Date of Divergence - Est. Time (MYA)
Accession Number
Sequence length (aa)
Sequence Identity (%)
Sequence Similarity (%)
n
m
Homo sapiens
Humans
Primates
0
NP_001027544.1
803
100
100
0
0.0
Macaca mulatta
Rhesus Macaque
Primates
29.44
AFE75666.1 (extended)
767
91.9
93.9
8.1
8.4
Fukomys damarensis
Damara Mole Rat
Rodentia
90
XP_010621546.2
753
73.6
79.3
26.4
30.7
Camelus ferus
Wild Bactrian Camel
Artiodactyla
94
XP_006175095.2
802
81.8
88.6
18.2
20.1
Odobenus rosmarus divergens
Pacific Walrus
Carnivora
96
XP_012418040.1
806
84.5
90.3
15.5
16.8
Mirounga leonina
Southern Elephant Seal
Carnivora
96
XP_034842573.1
806
83.7
89.8
16.3
17.8
Manis javanica
Malayan Pangolin
Pholidota
96
XP_017502667.1
584
49.4
53.0
50.6
70.5
Echinops telfairi
Lesser Hedgehog Tenrec
Afrosoricida
102
XP_030742207.1
419
31.9
38.9
68.1
114.3
Denticeps clupeoides
Denticle herring
Actinoptergyii/Clupeiformes
435
XP_028809248.1
3037
12.4
16.7
87.6
208.7
Beroe forskalii
Cigar comb jellies
Ctenophora/Beroida
540
AHA51259.1
212
12.0
18.2
88.0
212.0
Araneus ventricosus
Orb weaving Spider
Araneae
736
GBN07005.1
543
30.2
38.9
69.8
119.7
Capitella teleta
Segmented annelid worm
Annelida
797
ELT92884.1
537
31.3
43.3
68.7
116.2
Thelazia callipaeda
Parasitic nematode
Nematoda/Rhabditida
797
VDN04867.1
418
25.2
32.9
74.8
137.8
Drosophila melanogaster
Fruit flies
Diptera
797
NP_650197.1
501
24.4
34.8
75.6
141.1
Octopus sinensis
Common octopus
Octopada/Mollusca
797
XP_029652221.1
5045
6.8
9.2
93.2
268.8
Nematostella vectensis
Starlet Sea Anemone
Cnidaria/Anthozoa
824
EDO31838.1
482
30.7
42.6
69.3
118.1
Macrostomum lignano
Flatworm
Platyhelminthes/Macrostomida
824
PAA81016.1
477
27.0
35.6
73.0
130.9
Salpingoeca rosetta
Choanoflagellates
Choanoflagelletes
1023
XP_004989424.1
480
20.5
28.3
79.5
158.5
Rhizophagus clarus
Arbuscular mycorrhizal fungi
Fungi/Glomerales
1105
GBB86324.1
717
30.1
41.8
69.9
120.1
Salmonella enterica
Gram Negative Bacteria
Salmonella/Enterobacterales
4290
EDQ2188565.1
310
12.8
18.2
87.2
205.6
Clinical significance
C15orf54 was associated with hypertrophy-associated polymorphisms in heart failure risk[14] and Atherosclerosis risk.[15] C15orf54 was also positively correlated with higher survival rates in patients with gastric cancer.[16] It was also shown to be a locus of interest in determining the glomerular filtration rate in a pool of individuals with Mongolian ancestry[17]