Functional Consequences of Proline Mutations in the Cytoplasmic and Transmembrane Sectors of the Ca2+-ATPase of Sarcoplasmic Reticulum

Vilsen, Bente; Andersen, Johannes Lund; Clarke, David M.; MacLennan, David H.

doi:10.1016/s0021-9258(19)30039-0

Cited by 158 publications

(41 citation statements)

References 36 publications

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“…This would be likely to occur as proline residues often have structural roles, and the first three helices in SHST1 are separated by very small loops. Proline residues essential for function have been identified in transmembrane helices in a number of other transporters [7,[22][23][24][25]. In both the Pst phosphate transport system in E. coli [22] and a mammalian dopamine transporter [23], proline residues in tightly coupled helices play a role in transport, similar to the situation we have observed in SHST1.…”

Section: Discussionsupporting

confidence: 68%

Proline residues in two tightly coupled helices of the sulphate transporter, SHST1, are important for sulphate transport

et al. 2001

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The sulphate transporter SHST1, from Stylosanthes hamata, features three tightly coupled transmembrane helices which include proline residues that are conserved in most related transporters. We used site-directed mutagenesis and expression of the mutant transporters in yeast to test whether these proline residues are important for function. Four proline residues were replaced by both alanine and leucine. Only one of these proline residues, Pro-144, was essential for sulphate transport. However, mutation of either Pro-133 or Pro-160 resulted in a severe decrease in sulphate transport activity; this was due more to a decrease in transport activity than to a decrease in the amount of mutant SHST1 in the plasma membrane. These results suggest that all three proline residues are important for transport, and that the conformation of the three tightly coupled helices may play a critical role in sulphate transport. We also show that SHST1 undergoes a post-translational modification that is required for trafficking to the plasma membrane.

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Section: Discussionsupporting

confidence: 68%

Proline residues in two tightly coupled helices of the sulphate transporter, SHST1, are important for sulphate transport

et al. 2001

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“…The latter mutation occurs at a site in ATP2C1 corresponding to one in ATP2A2 (G310V) that is mutated in a patient with classical DD (patient 13 in Jacobsen et al, 1999); clearly this residue is crucial for Ca 2+ ATPase function within the context of epidermal disease. The proline residue equivalent to that of ATP2C1 mutation P201L was changed to an alanine residue in SERCA1 without discernible loss of Ca 2+ af®nity or transport (Vilsen et al, 1989). Investigations in ATP2C1 are required to see whether this residue plays a role critical only in this protein.…”

Section: Discussionmentioning

confidence: 99%

Hailey-Hailey Disease: Molecular and Clinical Characterization of Novel Mutations in the ATP2C1 Gene

Dobson‐Stone

Fairclough

Dunne

et al. 2002

Journal of Investigative Dermatology

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Hailey-Hailey disease is an autosomal dominant skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis. Mutations in ATP2C1, the gene encoding a novel, P-type Ca2+-transport ATPase, were recently found to cause Hailey-Hailey disease. In this study, we used conformation-sensitive gel electrophoresis to screen all 28 translated exons of ATP2C1 in 24 Hailey-Hailey disease families and three sporadic cases with the disorder. We identified 22 different mutations, 18 of which have not previously been reported, in 25 probands. The novel mutations comprise three nonsense, six insertion/deletion, three splice-site, and six missense mutations and are distributed throughout the ATP2C1 gene. Six mutations were found in multiple families investigated here or in our previous study. Haplotype analysis revealed that two of these are recurrent mutations that have not been inherited from a common ancestor. Comparison between genotype and phenotype in 23 families failed to yield any clear correlation between the nature of the mutation and clinical features of Hailey-Hailey disease. The extensive interfamilial and intrafamilial phenotypic variability observed suggests that modifying genes and/or environmental factors may greatly influence the clinical features of this disease.

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“…Ca 2 þ transport assay Ca 2 þ transport was measured at 371C by the rapid millipore ¢ltration technique described previously (Vilsen et al, 1989). Brie£y, Ca 2 þ transport activity was initiated by addition of microsomes in a reaction mixture containing 20 mM 3 -Morpholinopropanesulfonic acid (pH 6.8), 100 mM KCl, 5 mM MgCl 2 , 5 mM potassium oxalate, 5 mM ATP, 0.5 mM ethylenediaminetetraacetic acid, 10 5 Bq 45 Ca 2 þ per ml, and 0.45 mM CaCl 2 to set the free Ca 2 þ concentration at 3.6 mM.…”

Section: Methodsmentioning

confidence: 99%

Acrokeratosis Verruciformis of Hopf is Caused by Mutation in ATP2A2: Evidence That it is Allelic to Darier's Disease

Dhitavat¹,

Macfarlane²,

Dode³

et al. 2003

Journal of Investigative Dermatology

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Acrokeratosis verruciformis of Hopf is a localized disorder of keratinization affecting the distal extremities. Onset is early in life and the disease is inherited in an autosomal dominant fashion. Although histology of acrokeratosis verruciformis lesions shows no evidence of dyskeratosis, a possible relationship with Darier's disease has long been postulated on the basis of clinical similarity. ATP2A2 encoding the sarco(endo)plasmic reticulum Ca2+ ATPase2 pump has been identified as the defective gene in Darier's disease. In this report, we studied a family affected with acrokeratosis verruciformis in six generations and identified a heterozygous P602L mutation in ATP2A2. This mutation predicts a nonconservative amino acid substitution in the ATP binding domain of the molecule. The mutation segregates with the disease phenotype in the family and was not found in 50 controls. Moreover, functional analysis of the P602L mutant showed that it has lost its ability to transport Ca2+. This result demonstrates loss of function of the sarco(endo)plasmic reticulum Ca2+ ATPase2 mutant in acrokeratosis verruciformis, thus providing evidence that acrokeratosis verruciformis and Darier's disease are allelic disorders.

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Functional Consequences of Proline Mutations in the Cytoplasmic and Transmembrane Sectors of the Ca2+-ATPase of Sarcoplasmic Reticulum

Cited by 158 publications

References 36 publications

Proline residues in two tightly coupled helices of the sulphate transporter, SHST1, are important for sulphate transport

Proline residues in two tightly coupled helices of the sulphate transporter, SHST1, are important for sulphate transport

Hailey-Hailey Disease: Molecular and Clinical Characterization of Novel Mutations in the ATP2C1 Gene

Acrokeratosis Verruciformis of Hopf is Caused by Mutation in ATP2A2: Evidence That it is Allelic to Darier's Disease

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