ATP5SL

DMAC2
Identifiers
AliasesDMAC2, ATP5SL, ATP5S like, distal membrane arm assembly complex 2, distal membrane arm assembly component 2
External IDsOMIM: 617262; MGI: 1913599; HomoloGene: 9973; GeneCards: DMAC2; OMA:DMAC2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

55101

66349

Ensembl

ENSG00000105341

ENSMUSG00000057229

UniProt

Q9NW81

Q9D7K5

RefSeq (mRNA)

NM_001290487
NM_025504

RefSeq (protein)

NP_001277416
NP_079780

Location (UCSC)Chr 19: 41.43 – 41.44 MbChr 7: 25.32 – 25.32 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

ATP synthase subunit s-like protein is a protein that in humans is encoded by the DMAC2 gene.[5] It has a role in the assembly of the distal portion of the Mitochondiral Respiratory Complex 1 (NADH: ubiquinone oxidoreductase) membrane arm. Complex 1 is the largest respiratory complex of the mitochondrial electron transport chain.

Gene

ATP5SL’s preferred name is DMAC2, Distal membrane arm assembly complex 2. DMAC2 is on the minus strand of Chromosome 19 and spans 9400 base pairs.[6]

mRNA

There are 6 exons within ATP5SL's mRNA sequence and 12 known transcript variants that span between 1489 and 2515 nucleotides.[7]

The 3' untranslated region sequence has 8 large stem loops with 3 overlapping miRNA target binding sites: hsa-miR-4731-5p, hsa-miR-671-5p, and hsa-miR-4786-3p. This site is almost fully conserved in primates; it differs by one base pair. A secondary site of hsa-miR-4731-5p is fully conserved among Primates.

Caption text
miRNA name Target sequence Association
hsa-miR-4731-5p CCCCAGCA Tumor suppressive activity [8]
hsa-miR-671-5p GGCTTCC Tumor suppressor in breast cancer [9]
hsa-miR-4786-3p GGCTTCC Immune system; antiviral potential

Expression

It is ubiquitously expressed at moderate levels in all tissues, with occasional high expression levels in the heart and skeletal muscle.

Protein

There are 11 different isoforms[10]. DMAC2 Isoform 1 is the longest, with a predicted molecular weight of about 3.2 kDa and a theoretical isoelectric point of about 5.85, making it negatively charged under basic conditions. It is localized in the mitochondria.

Table 1. DMAC2 Isoform table. Data obtained from NCBI
Protein Isoform Accession ID Length (amino acids) Difference
1 NP_001161339 263
2 NP_001161340.1 191 Lacks an exon in the 3’ coding region. distinct C-terminus
3 NP_001161341.1 185 Different 5’ untranslated region length and protein coding region
4 NP_060505.2 257 Has an alternate in-frame exon in the 5' coding region
5 NP_001161343.1 230 Different N-termini
6 NP_001161342.1 158 Different N- and C-termini
7 NP_001307767.1 170 different 5’ Untranslated region length, translation initiation at a different start codon
8 NP_001307768.1 178 Missing multiple exons and 3' terminal exon extends past a splice site; different 3' coding region and 3' Untranslated region
9 NP_001307769.1 236 Lacks an alternate in-frame exon
10 NP_001307770.1 164 Missing two alternate exons in the coding region
11 NP_001307773.1 172 Distinct different N- and C- termini


Amino Acid Composition

Source:[11]

  • DMAC2 isoform 1 sequence contains 5 Threonines, which is fewer than the average human protein has.
  • It has no charged segments or charge clusters.
  • There are more acidic residues than basic ones.
  • No significant hydrophobic segments.

Regions

There are two different 15-amino acid segments that repeat a Leucine every third amino acid. DMAC2 isoform 1 contains a Leucine-rich repeat domain of unknown function, DUF7885, which spans 94 amino acids.[12] Leucine-rich repeats are commonly composed of 2-45 motifs of 20-30 residues in length.[13] This motif is highly conserved in ATP5SL’s strict and distant orthologs. It has no transmembrane domains.

Post-translational modification

ATP5SL is predicted to undergo phosphorylation at multiple Serine, Threonine, and Tyrosine sites.[14] The kinases associated with the phosphorylation sites are Protein kinase A, cdc1, cdc2, EGFR, andATM. Serines have the highest amount of predicted phosphorylation sites in ATP5SL.

It has 2 predicted propeptide cleavage sites at Arginines.[15] In order to establish a mature protein, these sections are cut off and inactivated by proteases. Propeptides assist precursor proteins in remaining inactive until the right signal to move to their correct destination.[16]

Predicted propeptide cleavage sites in ATP5SL.
Position Context Score
45 GNQKKKR~TI 0.796
255 GPEEQPR~DT 0.627

Cleavage site is indicated by ~.

It contains a Mitochondrial transit peptide sorting signal at the N-terminus,[17] which directs proteins to the Chloroplast and Mitochondria. There are no signal proteins present.

There are no N-glycosylation or N-acetylation sites.

Protein Structure

Tertiary structure can be visualized using I-Tasser and iCn3D. ATP5SL's structure is indicative of a Leucine-rich repeat region, which typically folds into a horseshoe (or arc) shape with a parallel beta-sheet on the concave face and different secondary helices structures on the convex face.[18] ATP5SL has alpha helices on the convex face and 3 parallel beta-sheets on the concave face.

ATP5SL is predicted to be soluble or globular,[19] it can diffuse through aqueous environments.[20] Commonly, in globular proteins, hydrophobic amino acid side chains are buried in the interior of the protein, and the hydrophilic amino acid side chains lie on the surface exposed to the water.[21] Interactions between amino acid residues stabilize globular protein structure.

Protein Interactions

Table 3. Proteins that are found to interact with ATP5SL
Protein IDs Identification Function Subcellular Location
Mitochondria-localized glutamic acid-rich protein MGARP Affinity Capture-MS Regulates the morphology and distribution of mitochondria Mitochondria
FAD-dependent oxidoreductase domain containing 1 FOXRED1 Cross-Linking Involved in the mid-late stages of complex I assembly Mitochondria
Transmembrane Protein 70 TMEM70 Textmining Biogenesis of mitochondrial ATP synthase Mitochondria
Distal membrane-arm assembly complex protein 1 DMAC1 GEO microarray Co-expression Involved in the assembly of the distal region of complex I) Mitochondria
Mov10 RISC complex RNA helicase MOV10 Affinity Capture-RNA Promotes type I interferon production in innate antiviral immunity Cytosol
Kelch-like family member 20 KLHL20 Two-Hybrid Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex Cytosol, Golgi Apparatus
Kinesin family member 14 KIF14 Affinity Capture-MS Regulates cell growth through regulation of cell cycle progression and cytokinesis Example

Conceptual translation

Shown on the right is a PDF of the full conceptual translation of Human DMAC2 isoform 1 (full mRNA) with annotations on the right side and an annotation legend below.

Homology

There are no known paralogs to this gene. DMAC2 evolutionary history spans approximately 563 million years (MYA); it was first found in jawless vertebrates, but not invertebrates.

Mammal, non-primate orthologs sequence identity ranged from 52% to 74%, and 72-86% sequence similarity.

Caption text
taxonomic group Genus and species Common name taxonomic order median date of divergence from humans (MYA) Accession # Sequence Length (aa) Sequence identity (%)

Sequence similarity(%)

Mammalia Homo Sapiens Human Primates 0 NP_001161339.1 263 100 100
Mammalia Macaca fascicularis Crab Eating macaque Primates 28.8 XP_045236960.1 253 89 92
Mammalia Carlito syrichta Philippine tariser Primates 69 XP_021568406.1 302 77 88
Mammalia Mus musculus House mouse Rodentia 87 NP_001277416.1 250 67 82
Mammalia Bos taurus Domestic cattle Ungulates 94 NP_001258937.1 301 74 86
Mammalia Macrotis lagotis Bilby Peramelemorphia 160 XP_074075255.1 281 52 72
Reptilia Ciconia boyciana Oriental stork Ciconiiformes 319 XP_072704911.1 260 46 63
Reptilia Rhineura floridana Florida worm lizard Squamata 319 XP_061454037.1 271 47 64
Reptilia Trachemys scripta elegans Red-eared terrapin Testudines 319 XP_034648456.1 229 47 63
Reptilia Anas acuta Northern Pintail Anseriformes 319 XP_068524425.1 235 50 67
Amphibia Rhinatrema bivittatum Two lined caecilian Gumnophiona 352 XP_029475261.1 280 52 72
Amphibia Ascaphus truei Tailed frog Anura 352 XP_075463000.1 212 48 67
Actinopterygii Conger conger Conger eel Anguilliformes 429 XP_061073726.1 273 43 62
Actinopterygii Acipenser ruthenus Sterlet sturgeon Acipenseriformes 429 XP_033914069.3 262 48 64
Chondrichthyes Scyliorhinus canicula Small-spotted catshark Carcharhiniformes 462 XP_038642055.1 262 48 66
Chondrichthyes Narcine bancroftii Caribbean electric ray Torpediniformes 462 XP_069763551.1 261 54 70
Cephalaspidomorphi Lethenteron reissneri Far Eastern brook lamprey Petromyzontiformes 563 XP_061415248.1 245 45 65

Clinical Significance

Publications and databases have linked or associated ATP5SL with diseases related to the dysfunction of Complex I.

In Ovarian cancer, there is a large copy number variation on chromosome 19, which includes the deletion of ATP5SL.[22] In Breast cancer, there is a copy number variation that is thought to either gain or lose a copy of ATP5SL.[23]

SNPs

There are 5,917 catalogued SNPs on the NCBI Variation Viewer, many of which are intron variants. rs7259208 is associated with Type 2 diabetes in African Americans, but its role in the pathophysiology of Type 2 diabetes remains unknown.[24]


References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000105341 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000057229 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: ATP5S-like".
  6. ^ Link text, DMAC2 on Gene Cards.
  7. ^ DMAC2 mRNA on NCBI NCBI gene browser.
  8. ^ link text, Chang Chang and Meilin Xu (March 2022).
  9. ^ miR-671-5p inhibits epithelial-to-mesenchymal transition by downregulating FOXM1 expression in breast cancer, Tan et al (Jan 2016).
  10. ^ DMAC2 NCBI Reference Sequences, NCBI.
  11. ^ DMAC2 SAPS output from EMBL-EBI, SAPS.
  12. ^ DMAC2 isoform 1, MotifFinder.
  13. ^ Leucine-rich repeat domain superfamily, InterPro.
  14. ^ Phosphorylation site prediction, NetPhos-3.1.
  15. ^ ProP-1.0 Output,DTU Health Teach.
  16. ^ Computational analysis of propeptide-containing proteins and prediction of their post-cleavage conformation changes, Jimin Pei, Lisa N. Kinch, Qian Cong (May 2024).
  17. ^ DeepLOC Output, DTU Health.
  18. ^ Structural principles of leucine-rich repeat (LRR) proteins, Purejav Enkhbayar, Masakatsu Kamiya, Mitsuru Osaki, Takeshi Matsumoto, Norio Matsuhima (Feb 2004).
  19. ^ DeepLOC Output, DTU Health.
  20. ^ PubMed, Beznoussenko et al., (May 2014).
  21. ^ Diagnostic Molecular Biology Chapter 4, Chang-Hui Shen (2019).
  22. ^ Copy number Variation for Ovarian Cancer MalaCards Human Disease Database.
  23. ^ Copy number Variation for Breast Cancer MalaCards Human Disease Database.
  24. ^ Mapping Adipose and Muscle Tissue Expression Quantitative Trait Loci in African Americans to Identify Genes for Type 2 Diabetes and Obesity, Satria P Sajuthi et al. (May 2016).

Further reading

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