title: Multiple effects of SERCA2b mutations associated with Darier's disease.
abstract: Darier's disease (DD) is an autosomal dominant disorder caused by mutations in the ATP2A2 gene, encoding sarco/endoplasmic reticulum Ca2+-ATPase pump type 2b isoform (SERCA2b). Although >100 mutations in the ATP2A2 gene were identified, no apparent relation between genotype/phenotype emerged. In this work, we analyzed 12 DD-associated mutations from all of the regions of SERCA2b to study the underlying pathologic mechanism of DD and to elucidate the role of dimerization in SERCA2b activity. Most mutations markedly affected protein expression, partially because of enhanced proteasome-mediated degradation. All of the mutants showed lower activity than the wild type pump. Notably, several mutants that cause relatively severe phenotype of DD inhibited the activity of the endogenous and the co-expressed wild type SERCA2b. Importantly, these effects were not attributed to changes in passive Ca2+ leak, inositol 1,4,5-trisphosphate receptor activity, or sensitivity to inositol 1,4,5-trisphosphate. Rather, co-immunoprecipitation experiments showed that SERCA2b monomers interact to influence the activity of each other. These findings reveal multiple molecular mechanisms to account for the plethora of pathologic states observed in DD and provide the first evidence for the importance of SERCA2b dimerization in pump function in vivo.
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. Shmuel.Muallen@UTSouthwestern.edu
authors.forename: Wooin
authors.initials: W
authors.lastname: Ahn
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
authors.forename: Kyung Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Shmuel
authors.initials: S
authors.lastname: Muallem
mesh_terms: D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D007644:Darier Disease / Q000235:genetics* / Q000378:metabolism; D019281:Dimerization; D005838:Genotype; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007668:Kidney / Q000166:cytology; D009097:Multienzyme Complexes / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
chemical_list: D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009097:Multienzyme Complexes; D018160:Receptors, Cytoplasmic and Nuclear; D015544:Inositol 1,4,5-Trisphosphate; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D000252:Calcium-Transporting ATPases; D002118:Calcium