The Retinal Rod Na+/Ca2+,K+Exchanger Contains a Noncleaved Signal Sequence Required for Translocation of the N Terminus

McKiernan, C J; Friedlander, Martin

doi:10.1074/jbc.274.53.38177

Cited by 7 publications

(7 citation statements)

References 24 publications

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“…SLC24A1 encodes a sodium/calcium, potassium exchanger (NCKX1) that removes intracellular calcium by exchanging four sodium ions for one calcium and one potassium [128]. The p.Leu26Phe substitution identified in MS patients is part of an uncleaved signal peptide sequence required for efficient membrane targeting and integration [129]. This signal sequence is highly conserved in mammals, including the p.Leu26 residue (Fig 4), but no homologous region exist in paralogs.…”

Section: Resultsmentioning

confidence: 99%

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

et al. 2019

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Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways ( PLAU , MASP1 , C2 ), inflammasome assembly ( NLRP12 ), Wnt signaling ( UBR2 , CTNNA3 , NFATC2 , RNF213 ), nuclear receptor complexes ( NCOA3 ), and cation channels and exchangers ( KCNG4 , SLC24A6 , SLC8B1 ). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.

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Section: Resultsmentioning

confidence: 99%

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

et al. 2019

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“…Under these conditions, the corresponding region in the AChE translation product would become a transmembrane domain in an N-terminally extended (and 16% larger) AChE variant (hN-AChE). Analogous situations have been described for the asialoglycoprotein receptor (20), adrenal dopamine ␤-monooxygenase (22), ␣-neurexin (an extended form of ␤-neurexin) (23), retinal RodX exchanger (24), prion protein (25), and cyclooxygenase (26). COX-1, the classic cyclooxygenase form, includes a signal peptide at the N terminus.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial Complexity of 5′ Alternative Acetylcholinesterase Transcripts and Protein Products

Meshorer

Toiber

Zurel

et al. 2004

Journal of Biological Chemistry

106

128

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To explore the scope and significance of alternate promoter usage and its putative inter-relationship to alternative splicing, we searched expression sequence tags for the 5 region of acetylcholinesterase (ACHE) genes. Three and five novel first exons were identified in human and mouse ACHE genes, respectively. Reverse transcription-PCR and in situ hybridization validated most of the predicted transcripts, and sequence analyses of the corresponding genomic DNA regions suggest evolutionarily conserved promoters for each of the novel exons identified. Distinct tissue specificity and stress-related expression patterns of these exons predict combinatorial complexity with known 3 alternative AChE mRNA transcripts. Unexpectedly one of the 5 exons encodes an extended N terminus in-frame with the known AChE sequence, extending the increased complexity to the protein level. The resultant membrane variant(s), designated N-AChE, is developmentally regulated in human brain neurons and blood mononuclear cells. Alternative promoter usage combined with alternative splicing may thus lead to stress-dependent combinatorial complexity of AChE mRNA transcripts and their protein products.Alternative splicing and alternate promoter usage both expand the complexity of gene products. While the massive contribution of alternative splicing to such expansion is widely recognized (1), less is known about the scope and significance of alternate promoter usage. Moreover the directionality of transcription processes raises the yet unresolved possibility that these two phenomena are inter-related, namely that the choice of the first exon determines downstream splice choices (2). The recent accumulation of genomic and gene expression data bases together with the development of sophisticated bioinformatic tools makes these questions amenable for experimental analysis as multiple gene products display both alternate promoter usage and alternative splicing variations. By alignment of expression sequence tags (ESTs) 1 against genomic sequences, for example, it is possible to explore the different alternatively spliced products of a single gene (3, 4). However, EST data bases are biased toward the 3Ј end of mRNAs and occasionally contain genomic contaminations that may cause misinterpretation of the genomic information (5). To correctly evaluate the inter-relationship between alternate promoter usage and alternative splicing, it is therefore necessary to characterize the identified variants using traditional molecular biology tools at the RNA level and, if applicable, at the protein level as well.The acetylcholine-hydrolyzing enzyme acetylcholinesterase (AChE) provides an adequate example for such a study. AChE pre-mRNA is subject to stimulus-induced 3Ј alternative splicing (6), and previous evidence has suggested that it is also subject to alternate promoter usage (7,8). We analyzed the genomic regions flanking the human and mouse ACHE genes and found an unexpected, evolutionarily conserved diversity of alternate exons at their 5Ј end. The newly id...

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“…In one study, it was suggested that, like NCX1, bovine rod NCKX1 contained a cleavable N-terminal signal sequence, since N-terminal sequencing of the purified bovine rod NCKX1 led to a sequence starting at Asp66 (3). In contrast, analysis of bovine rod NCKX1 polypeptides obtained in a cell-free system showed no evidence for cleavage but suggested that the N-terminal sequence was important for a proper topology, inferred by glycosylation of the extracelluar loop (11).…”

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confidence: 99%

Signal Sequence Cleavage and Plasma Membrane Targeting of the Retinal Rod NCKX1 and Cone NCKX2 Na⁺/Ca²⁺−K⁺Exchangers

Kang

Schnetkamp

2003

Biochemistry

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Retinal rod and cone photoreceptors express two distinct Na(+)/Ca(2+)-K(+) exchanger (NCKX) gene products. Both the rod NCKX1 and cone NCKX2 are polytopic membrane proteins thought to contain a putative cleavable signal peptide. A cleavable signal peptide is unusual for plasma membrane proteins; moreover, predictive algorithms suggest the presence of a cleavable signal peptide for all rod NCKX1 proteins and a noncleavable signal anchor for the cone NCKX2 proteins. In this study we have placed a peptide tag at different positions of the NCKX sequence to examine whether the putative signal sequence is indeed cleaved in either NCKX1 or NCKX2 proteins expressed in heterologous systems. The signal peptide was found to be, at least in part, cleaved in dolphin rod NCKX1 and in chicken and human cone NCKX2 expressed in HEK293 cells; no signal peptide cleavage was observed for chicken rod NCKX1 despite the fact that the SignalP predictive algorithm assigned this sequence to have the highest likelihood for a cleavable signal peptide among the three NCKX sequences tested here. For the two NCKX proteins that contained a cleavable signal peptide, only cleaved NCKX protein was found in the plasma membrane of HEK293 cells. Deletion of the signal sequence in both dolphin rod NCKX1 or cone NCKX2 did not affect NCKX protein synthesis but did disrupt plasma membrane targeting as judged from abolition of NCKX function and from lack of surface biotinylation. These results are consistent with delayed signal peptide cleavage for the rod and cone NCKX proteins.

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The Retinal Rod Na+/Ca2+,K+Exchanger Contains a Noncleaved Signal Sequence Required for Translocation of the N Terminus

Cited by 7 publications

References 24 publications

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

Combinatorial Complexity of 5′ Alternative Acetylcholinesterase Transcripts and Protein Products

Signal Sequence Cleavage and Plasma Membrane Targeting of the Retinal Rod NCKX1 and Cone NCKX2 Na⁺/Ca²⁺−K⁺Exchangers

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The Retinal Rod Na+/Ca2+,K+Exchanger Contains a Noncleaved Signal Sequence Required for Translocation of the N Terminus

Cited by 7 publications

References 24 publications

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

Combinatorial Complexity of 5′ Alternative Acetylcholinesterase Transcripts and Protein Products

Signal Sequence Cleavage and Plasma Membrane Targeting of the Retinal Rod NCKX1 and Cone NCKX2 Na+/Ca2+−K+Exchangers

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Signal Sequence Cleavage and Plasma Membrane Targeting of the Retinal Rod NCKX1 and Cone NCKX2 Na⁺/Ca²⁺−K⁺Exchangers