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Palmitoylation of the Na/Ca exchanger cytoplasmic loop controls its inactivation and internalization during stress signaling.

Reilly L, Howie J, Wypijewski K, Ashford ML, Hilgemann DW, Fuller W - FASEB J. (2015)

Bottom Line: Surprisingly, palmitoylation does not influence trafficking or localization of NCX1 to surface membranes, nor does it strongly affect the normal forward or reverse transport modes of NCX1.However, exchangers that cannot be palmitoylated do not inactivate normally (leading to substantial activity in conditions when wild-type exchangers are inactive) and do not promote cargo-dependent endocytosis that internalizes 50% of the cell surface following strong G-protein activation or large Ca transients.The palmitoylated cysteine in NCX1 is found in all vertebrate and some invertebrate NCX homologs.

View Article: PubMed Central - PubMed

Affiliation: *Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, United Kingdom; and Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

No MeSH data available.


Related in: MedlinePlus

Conservation of the NCX palmitoylation site. A) The hydrophilic cytosolic loops of representative members of the cation/Ca2+ exchanger superfamily were aligned using Clustal Omega (67). The NCX palmitoylated cysteine (boxed) is not conserved in other branches of this superfamily. B) NCX family members from vertebrates and invertebrates were aligned using Clustal Omega. The NCX1 palmitoylated cysteine (boxed) is conserved among all NCX isoforms in all vertebrates, as well as squid and the Drosophila exchanger Calx, but it is not present in NCX1 or NCX3 from C. elegans. In NCX variants that contain the palmitoylated cysteine, glutamate at −6, proline at −2, tyrosine at +3, and histidine at +6 are 100% conserved.
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Figure 8: Conservation of the NCX palmitoylation site. A) The hydrophilic cytosolic loops of representative members of the cation/Ca2+ exchanger superfamily were aligned using Clustal Omega (67). The NCX palmitoylated cysteine (boxed) is not conserved in other branches of this superfamily. B) NCX family members from vertebrates and invertebrates were aligned using Clustal Omega. The NCX1 palmitoylated cysteine (boxed) is conserved among all NCX isoforms in all vertebrates, as well as squid and the Drosophila exchanger Calx, but it is not present in NCX1 or NCX3 from C. elegans. In NCX variants that contain the palmitoylated cysteine, glutamate at −6, proline at −2, tyrosine at +3, and histidine at +6 are 100% conserved.

Mentions: NCX1 is a member of the cation/Ca exchanger superfamily, which is defined by the presence of highly conserved α-repeat regions within 2 membranous hydrophobic domains, which are separated by a hydrophilic cytosolic loop rich in acidic amino acids. This superfamily of 147 transporters from both eukaryotes and prokaryotes consists of 5 distinct protein families (66). We used Clustal Omega (67) to align the hydrophilic regions of representative members (mammalian, where available) of each family (Fig. 8A); the palmitoylated cysteine in NCX1 is not found in the other mammalian family members (Na/K/Ca exchangers or the mitochondrial exchanger NCLX), or in the H/Ca exchanger or YRBG families. No homologous position exists in the crystallized NCX homolog NCX_Mj, which is short (7 amino acids) and disordered (21).


Palmitoylation of the Na/Ca exchanger cytoplasmic loop controls its inactivation and internalization during stress signaling.

Reilly L, Howie J, Wypijewski K, Ashford ML, Hilgemann DW, Fuller W - FASEB J. (2015)

Conservation of the NCX palmitoylation site. A) The hydrophilic cytosolic loops of representative members of the cation/Ca2+ exchanger superfamily were aligned using Clustal Omega (67). The NCX palmitoylated cysteine (boxed) is not conserved in other branches of this superfamily. B) NCX family members from vertebrates and invertebrates were aligned using Clustal Omega. The NCX1 palmitoylated cysteine (boxed) is conserved among all NCX isoforms in all vertebrates, as well as squid and the Drosophila exchanger Calx, but it is not present in NCX1 or NCX3 from C. elegans. In NCX variants that contain the palmitoylated cysteine, glutamate at −6, proline at −2, tyrosine at +3, and histidine at +6 are 100% conserved.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608915&req=5

Figure 8: Conservation of the NCX palmitoylation site. A) The hydrophilic cytosolic loops of representative members of the cation/Ca2+ exchanger superfamily were aligned using Clustal Omega (67). The NCX palmitoylated cysteine (boxed) is not conserved in other branches of this superfamily. B) NCX family members from vertebrates and invertebrates were aligned using Clustal Omega. The NCX1 palmitoylated cysteine (boxed) is conserved among all NCX isoforms in all vertebrates, as well as squid and the Drosophila exchanger Calx, but it is not present in NCX1 or NCX3 from C. elegans. In NCX variants that contain the palmitoylated cysteine, glutamate at −6, proline at −2, tyrosine at +3, and histidine at +6 are 100% conserved.
Mentions: NCX1 is a member of the cation/Ca exchanger superfamily, which is defined by the presence of highly conserved α-repeat regions within 2 membranous hydrophobic domains, which are separated by a hydrophilic cytosolic loop rich in acidic amino acids. This superfamily of 147 transporters from both eukaryotes and prokaryotes consists of 5 distinct protein families (66). We used Clustal Omega (67) to align the hydrophilic regions of representative members (mammalian, where available) of each family (Fig. 8A); the palmitoylated cysteine in NCX1 is not found in the other mammalian family members (Na/K/Ca exchangers or the mitochondrial exchanger NCLX), or in the H/Ca exchanger or YRBG families. No homologous position exists in the crystallized NCX homolog NCX_Mj, which is short (7 amino acids) and disordered (21).

Bottom Line: Surprisingly, palmitoylation does not influence trafficking or localization of NCX1 to surface membranes, nor does it strongly affect the normal forward or reverse transport modes of NCX1.However, exchangers that cannot be palmitoylated do not inactivate normally (leading to substantial activity in conditions when wild-type exchangers are inactive) and do not promote cargo-dependent endocytosis that internalizes 50% of the cell surface following strong G-protein activation or large Ca transients.The palmitoylated cysteine in NCX1 is found in all vertebrate and some invertebrate NCX homologs.

View Article: PubMed Central - PubMed

Affiliation: *Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, United Kingdom; and Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

No MeSH data available.


Related in: MedlinePlus