Alternative titles; symbolsCutA, E. COLI, HOMOLOG OFDIVALENT CATION TOLERANCE PROTEIN CUTAACETYLCHOLINESTERASE-ASSOCIATED PROTEIN; ACHAPCHROMOSOME 6 OPEN READING...
Alternative titles; symbols
HGNC Approved Gene Symbol: CUTA
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38): 6:33,416,441-33,418,106 (from NCBI)
CUTA functions in cellular copper sensitivity and in the processing and trafficking of membrane proteins (Zhao et al., 2012).
▼ Cloning and Expression
By peptide sequencing proteins that copurified with acetylcholinesterase (ACHE; 100740) from membrane fractions of human caudate nucleus, followed by PCR of a caudate nucleus cDNA library and screening a human fetal brain cDNA library, Navaratnam et al. (2000) cloned CUTA. The deduced 136-amino acid protein has a calculated molecular mass of approximately 14 kD. It has a possible N-terminal transmembrane domain, 3 N-glycosylation sites, 2 myristoylation sites, a glycosaminoglycan-binding site, and several phosphorylation sites. CUTA shares 2 regions of conservation with the E. coli protein CutA, including 2 cysteines. Northern blot analysis detected a 1.3-kb transcript in whole adult brain, in all brain regions examined, and in all peripheral tissues examined. EST database analysis revealed transcripts with alternative 5-prime sequences.
By database analysis, Perrier et al. (2000) identified 4 splice variants of human CUTA encoding 3 isoforms with different N termini.
Yang et al. (2009) identified 5 splice variants of human CUTA that encode isoforms of 198 (isoform 1), 156 (isoform 2), and 179 (isoform 3) residues that differ only at their N termini. The sequence of isoform 2, which is encoded by 3 of the 5 transcripts, is contained within the other 2 isoforms and includes a predicted mitochondrial targeting cleavage site. PCR amplification of a sequence common to all variants detected CUTA expression in all 18 human tissues examined, with highest expression in bladder, followed by liver and prostate. RT-PCR detected variable CUTA expression in several human cell lines. Overexpression of a cDNA encoding CUTA isoform 2 resulted in CUTA expression in perinuclear region and mitochondria, as well as in a filamentous cytosolic pattern. Cross-linking experiments revealed that isoform 2 formed trimers and possibly heteropolymers.
Zhao et al. (2012) found that translation of human CUTA can begin at met1 (M1), yielding isoform 1, as well as at M43 or M63 (numbering of isoform 1), which are found in all 3 isoforms. M43 is the initiation site of isoform 2. Western blot analysis of fractionated HEK293 cells identified endogenous heavy (H) and light (L) CUTA proteins with apparent molecular masses of 20 and 13 kD, respectively. The H component represented full-length isoform 1 and was found in the membrane fraction. The L component, representing CUTA initiating at M43 (i.e., isoform 2) and at M63, was found in the cytosolic fraction. Alkali extraction revealed that full-length CUTA isoform 1 is likely integrated into the membrane via its N-terminal extension.
▼ Gene Function
Perrier et al. (2000) found that knockdown of Cuta in N18TG2 murine neuroblastoma cells via antisense RNA eliminated cell surface accumulation of Ache.
Brain accumulation of neurotoxic beta-amyloid (A-beta) peptide, which is derived from sequential cleavage of APP (104760) by beta (BACE1; 604252)- and gamma (see PSEN1, 104311)-secretases in the Golgi/trans-Golgi network (TGN), is central to Alzheimer disease (AD; 104300) pathogenesis. Zhao et al. (2012) found that full-length CUTA isoform 1 interacted with BACE1 mainly in the Golgi/TGN. Coimmunoprecipitation and mutation analyses revealed that the N-terminal domain of CUTA isoform 1 interacted with the transmembrane domain of BACE1. Cytosolic isoforms of CUTA did not interact with BACE1. Overexpression of CUTA isoform 1 reduced BACE1-mediated APP processing in the Golgi/TGN and reduced A-beta secretion. Knockdown of CUTA isoform 1 reduced cell surface BACE1 and increased APP processing and A-beta secretion. Zhao et al. (2012) concluded that CUTA isoform 1 is a BACE1-interacting protein that mediates intracellular trafficking of BACE1 and inhibits BACE1-dependent processing of APP to A-beta.
Hou et al. (2015) found that overexpression of full-length human CUTA isoform 1 increased copper content in mouse neuroblastoma N2a cells in a dose-dependent manner. Copper increased Cuta mRNA and protein in a dose-dependent manner, suggesting positive feedback. In AD model mouse cells, copper and CUTA isoform 1 up- and downregulated APP processing, respectively. Whereas copper increased App expression and processing, CUTA isoform 1 reduced App processing via Bace1, but it had no effect on App expression. Both copper and Cuta were downregulated in hippocampus of AD model mice compared with controls.
▼ Gene Structure
Perrier et al. (2000) determined that the CUTA gene has 6 exons and spans approximately 20 kb.
By somatic cell hybrid analysis, YAC analysis, and FISH, Navaratnam et al. (2000) mapped the CUTA gene to chromosome 6p21.32-p21.2, adjacent to the SYNGAP1 (603384) gene.
Hartz (2016) mapped the CUTA gene to chromosome 6p21.32 based on an alignment of the CUTA sequence (GenBank AF106943) with the genomic sequence (GRCh38).