ATP synthase subunit s-like protein is a protein that in humans is encoded by the DMAC2gene.[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.
Normal RNA expression of DMAC2 in 27 various human tissues. Graph obtained from DMAC2 NCBI gene pageNCBI GEO Entry on ATP5SL from Normal tissue expression profiling (HG-U95E)
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
Compositional analysis of Human DMAC2 isoform 1 protein made via SAPS
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.
Tertiary structure of DMAC2 isoform 1 made via icn3d
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
Regulates cell growth through regulation of cell cycle progression and cytokinesis
Example
Conceptual translation
Conceptual translation of ATP5SL by Berit Hansen
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.
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]
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