137 126

Cited 54 times in

Multiple Effects of SERCA2b Mutations Associated with Darier's Disease

Authors
 Wooin Ahn  ;  Min Goo Lee  ;  Shmuel Muallem  ;  Kyung Hwan Kim 
Citation
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.278(23) : 20795-20801, 2003 
Journal Title
 JOURNAL OF BIOLOGICAL CHEMISTRY 
ISSN
 0021-9258 
Issue Date
2003
MeSH
Calcium/metabolism ; Calcium Channels/metabolism ; Calcium-Transporting ATPases/chemistry ; Calcium-Transporting ATPases/genetics* ; Calcium-Transporting ATPases/metabolism* ; Cells, Cultured ; Cysteine Endopeptidases/metabolism ; Darier Disease/genetics* ; Darier Disease/metabolism ; Dimerization ; Genotype ; Humans ; Inositol 1,4,5-Trisphosphate/metabolism ; Inositol 1,4,5-Trisphosphate Receptors ; Kidney/cytology ; Multienzyme Complexes/metabolism ; Mutagenesis, Site-Directed ; Phenotype ; Proteasome Endopeptidase Complex ; Receptors, Cytoplasmic and Nuclear/metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases
Keywords
12670936
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.
Files in This Item:
T200303941.pdf Download
DOI
10.1074/jbc.M301638200
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Hwan(김경환)
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/113705
사서에게 알리기
  feedback

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse