PAAT (protein associated with ABC transporters), also known as C10orf88 (chromosome 10 open reading frame 88), is a human protein encoded by the gene of the same name. It contains an ABC transporter domain predicted to associate with Type II ABC transporters. PAAT physically interacts with mitochondrial inner membrane ABC transporters and has a demonstrated role in ferric nutrient transport and heme biosynthesis. It is primarily expressed in the cerebral cortex, testis, and thymus, and localizes to the cytoplasm and nucleus. The gene has been associated with a rare form of Alzheimer's disease.
Evolution The earliest detectable ortholog of PAAT occurs in the subphylum Cephalochordata, specifically the European lancelet (Branchiostoma lanceolatum). This organism represents one of the most basal chordates, diverging from the vertebrate lineage approximately 588 million years ago (MYA), likely during the Cambrian period, though some phylogenetic models place this divergence as late as the Cretaceous. The lancelet ortholog shares only 21% sequence identity and 38% similarity with the human protein, with a corrected sequence divergence (CSD) of 156%. A comparable pattern holds in the Brook lamprey (Lampetra planeri), another early-branching chordate. No orthologs have been identified in invertebrates or prokaryotes, therefore PAAT appears to have a chordate-specific origin. PAAT is also absent in Sarcopterygii, despite being present in Actinopterygii; these groups differ in the presence of limb buds supported by articulated appendicular skeletons.
Sequence identity increases progressively with greater relatedness, with mammals averaging approximately 80% identity and the lowest overall CSD values. This pattern is consistent with purifying selection in lineages reliant on hemoglobin-based oxygen transport, given PAAT's proposed role in heme transport.
Compared to model proteins with well-characterized evolutionary rates, Cytochrome C (slow) and Fibrinogen alpha (fast), PAAT tracks closer to the fast-evolving end, with CSD values rising steeply with phylogenetic distance. This rapid divergence may reflect substantial functional variation across taxa, particularly given that heme transport roles appear prominent only in humans.
Class Seq Genus species Common name Taxon Date of Div (MYA) CorSeqDiv% Accession # Seq Length (aa) Seq ID (%) Seq Sim (%) Mammalia Hsa Homo sapiens Human Primates 0 0 NP_079218 445 100 100 Mammalia Mmu Mus musculus House mouse Rodentia 87 34.24903089 NP_080931.1 444 71 83 Mammalia Egl Eubalaena glacialis North Atlantic right whale Artiodactyl 94 22.31435513 XP_061048496.1 445 80 88 Mammalia Fca Felis catus House cat Carnivora 94 28.76820725 XP_038614534.1 444 75 85 Reptilia Eor Emys orbicularis European pond turtle Testudines 319 65.39264674 XP_065264191.1 462 52 68 Reptilia Pra Podarcis raffonei Aeolian wall lizard Lacertidae 319 69.31471806 XP_053244946.1 456 47 59 Reptilia Pca Pituophis catenifer Gopher snake Squamata 319 84.39700703 XP_070801900.1 454 43 59 Aves Gca Gymnogyps californianus Californian Condor Accipitriformes 319 75.50225843 XP_050754500.1 445 47 62 Aves Aph Agelaius phoeniceus Red-winged blackbird Passeriformes 319 82.09805521 XP_054493097.1 442 44 60 Aves Sca Struthio camelus Common ostrich Struthioniformes 319 84.39700703 XP_068807255.1 481 43 59 Amphibia Ame Ambystoma mexicanum Axolotl Urodela 352 107.8809661 XP_069468114.1 405 34 52 Amphibia Hya Hyla sarda Tyrrhenian tree frog Anura 352 110.8662625 XP_056385755.1 409 33 50 Amphibia Gse Geotrypetes seraphini Gaboon caecilian Gymnophiona 352 117.1182982 XP_033799666.1 371 31 45 Actinopterygii Psp Polyodon spathula American paddlefish Acipenseriformes 429 113.9434283 XP_041125204.1 433 32 51 Actinopterygii Eca Erpetoichthys calabaricus Reedfish Polypteriformes 429 146.967597 XP_028651065.1 438 23 45 Chondrichthyes Sti Stegostoma tigrinum Zebra shark Orectolobiformes 462 104.9822124 XP_048407415.1 439 35 52 Chondrichthyes Hfr Heterodontus francisci Horn shark Heterodontiformes 462 104.9822124 XP_067908923.1 441 35 50 Chondrichthyes Pja Pristiophorus japonicus Japanese sawshark Pristiophoriformes 462 107.8809661 XP_070732813.1 448 34 51 Petromyzontida Lpl Lampetra planeri Brook lamprey Petromyzontiformes 563 156.0647748 CAL9842239 499 21 35 Leptocardii Bla Branchiostoma lanceolatum European lancelet Branchiostomatidae 588 156.0647748 CAH1258791.1 414 21 38
Gene PAAT maps to chromosome 10 at cytogenetic locus 10q26.13. The gene spans 2,913 base pairs, comprises six exons and five introns, and encodes a 445-amino acid protein. No isoforms or splice variants have been identified. The mature mRNA is 1,497 nucleotides after splicing.
Transcription Factors The PAAT promoter contains binding sites for transcription factors associated with neural, immune, and reproductive contexts, consistent with the gene's expression profile. Key factors include NRF1, NR2C2, ELK4, ETV4, TFAP2A, and IRF3.
Protein PAAT functions as a novel ATPase, catalyzing ATP hydrolysis to regulate iron homeostasis. It contains two domains: a primary PAAT-like functional domain, and a secondary domain shared with other ABC transporters (designated "ABC Transport 1"). The ABC Transport 1 domain is predominantly beta sheet in secondary structure, while the C-terminus is largely alpha-helical. The protein has a theoretical isoelectric point of 6.0 and a predicted molecular weight of 49.2 kDa. No isoforms, disulfide bonds, or oligomerization have been identified.
Subcellular Localization PSORT II and DeepLoc both predict mainly nuclear localization (~60% confidence). Their secondary predictions branch: PSORT II favors mitochondrial (17.4%) and cytoplasmic (13%) signals, while DeepLoc assigns a stronger cytoplasmic probability (41%). No mitochondrial targeting sequences or cleavage sites have been detected, which weighs against exclusive mitochondrial localization. WoLF PSORT confirms nuclear and cytoplasmic localization as the two primary compartments. Analysis of known interacting proteins similarly clusters in the nucleus and cytoplasm, with mitochondria as a secondary possibility. These predictions are consistent across orthologs.
Protein Interactions PAAT is experimentally confirmed to interact with the mitochondrial inner membrane transporters ABCB7, ABCB8, and ABCB10, but not with ABCB1 or ABCG2. The STRING database identifies ten interacting proteins, five with experimental support: CLTC, GDI2, CCDC91, NCKAP1, and LILRB4. Most interactions are supported by co-expression data, except TEX9, NADSYN1, and LILRB4; all but POLR3F are text-mining supported. CLTC shows the most consistent co-expression across GEO microarray datasets. NADSYN1 and CYP2R1 may interact with PAAT through the vitamin D pathway.
Post-Translational Modifications PAAT is predicted to undergo phosphorylation at multiple serine residues (S11, S150, S201), lysine acetylation at K25,http://www.pail.biocuckoo.org/ and both N- and O-linked glycosylation. Degron motifs are present for both SCF-βTrCP1 and APC/C complexes. Functional motifs include 14-3-3 and SH2 binding sites, a PP1 phosphatase docking site, and a nuclear export signal. No signal peptides, lipid anchors, or organelle-targeting sequences have been detected.
Expression
Gene Expression PAAT is expressed across a broad range of human tissues, with elevated RNA levels in the testis (RPKM: 4.006), brain (RPKM: 1.916), and thymus per Human Protein Atlas RNA-seq data.
GEO datasets (GDS1096, GDS596, GDS3113) refine this picture further. GDS1096 shows broad brain expression with peaks in the thalamus and amygdala, alongside strong testis expression. GDS596 highlights olivary ganglia, superior cervical ganglia, and dorsal root ganglia. GDS3113 shows high expression in both the fetal brain and the testis. Total RNA-seq across 20 human tissues confirms significant expression in the cerebellum and thymus.
During fetal development, circular RNA data indicate early-stage PAAT expression across tissues without marked tissue specificity, in which a broad developmental role has been proposed.
Expression Quantitative Trait Loci (eQTLs) Several eQTLs regulate PAAT expression in a tissue-dependent manner. The variant chr10_123305622_C_A_b38 has a strong negative normalized effect score (NES: −1.0) in EBV-transformed lymphocytes, while chr10_123424873_AT_A_b38 shows a positive NES (0.86) in the esophagus muscularis. Brain-region variants, including those in the caudate and cerebellar hemisphere, exert negative regulatory effects. A testis-specific positive eQTL (NES: 0.39) is also present. Some eQTL-affected tissue, such as EBV-transformed lymphocytes and esophageal tissue, is not well represented at the protein level, which may reflect disease- or context-specific regulatory activity.
Protein Expression Immunohistochemical data show cytoplasmic staining in the testis and pancreas. Testicular expression is confined to subsets of cells within the seminiferous ducts; pancreatic expression is prominent in exocrine glandular cells. PaxDb places PAAT protein abundance near the proteome average, with higher levels in the brain, testis, lymph nodes, and ovaries, which are broadly consistent with the RNA expression data.
Condition-Specific Expression PAAT expression changes in several diseases and differentiation contexts. It is upregulated in redifferentiated podocytes derived from amniotic kidney progenitor cells, a finding that may indicate a role in renal cell maturation. In skeletal muscle from individuals with Myotonic Dystrophy Type 2 (DM2), PAAT is downregulated. It is also upregulated in peripheral blood mononuclear cells during Simian Immunodeficiency Virus (SIV) infection, particularly following PD-1 antibody treatment.
Function Yang et al. (2014) characterized PAAT as a trans-regulator of mitochondrial ABC transporters with intrinsic ATPase activity. The protein localizes to both the cytoplasm and mitochondria and selectively interacts with ABCB7, ABCB8, and ABCB10, but not ABCB1 or ABCG2, to modulate ferric nutrient transport and heme biosynthesis. Through ATP hydrolysis, PAAT maintains mitochondrial membrane potential and iron homeostasis; its depletion increases oxidative DNA damage and triggers cell death.
Clinical Significance
Alzheimer's Disease PAAT has been linked to a rare familial form of Alzheimer's disease designated AD15, which presents with amyloid-β plaques but lacks neurofibrillary tangles.
Vitamin D Metabolism PAAT has been proposed to interact with Cytochrome P450 during hydroxylation in the Vitamin D cycle, with dysregulation associated with Vitamin D deficiency.
Lipid Metabolism GWAS data associate PAAT variants rs7904973 and rs12246352 with lower LDL and Apolipoprotein B levels in humans. In rat models, PAAT has been linked to 2-Methylbutyryl-CoA Dehydrogenase Deficiency (a BCAA catabolism disorder) and craniosynostosis.
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