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Calcium binding, structural stability and guanylate cyclase activation in GCAP1 variants associated with human cone dystrophy

Dell'Orco, Daniele; Behnen, Petra; Linse, Sara LU and Koch, Karl-Wilhelm (2010) In Cellular and Molecular Life Sciences1997-01-01+01:00 67(6). p.973-984
Abstract
Guanylate cyclase activating protein 1 (GCAP1) is a neuronal Ca2+ sensor (NCS) that regulates the activation of rod outer segment guanylate cyclases (ROS-GCs) in photoreceptors. In this study, we investigated the Ca2+-induced effects on the conformation and the thermal stability of four GCAP1 variants associated with hereditary human cone dystrophies. Ca2+ binding stabilized the conformation of all the GCAP1 variants independent of myristoylation. The myristoylated wild-type GCAP1 was found to have the highest Ca2+ affinity and thermal stability, whereas all the mutants showed decreased Ca2+ affinity and significantly lower thermal stability in both apo and Ca2+-loaded forms. No apparent cooperativity of Ca2+ binding was detected for any... (More)
Guanylate cyclase activating protein 1 (GCAP1) is a neuronal Ca2+ sensor (NCS) that regulates the activation of rod outer segment guanylate cyclases (ROS-GCs) in photoreceptors. In this study, we investigated the Ca2+-induced effects on the conformation and the thermal stability of four GCAP1 variants associated with hereditary human cone dystrophies. Ca2+ binding stabilized the conformation of all the GCAP1 variants independent of myristoylation. The myristoylated wild-type GCAP1 was found to have the highest Ca2+ affinity and thermal stability, whereas all the mutants showed decreased Ca2+ affinity and significantly lower thermal stability in both apo and Ca2+-loaded forms. No apparent cooperativity of Ca2+ binding was detected for any variant. Finally, the nonmyristoylated mutants were still capable of activating ROS-GC1, but the measured cyclase activity was shifted toward high, nonphysiological Ca2+ concentrations. Thus, we conclude that distorted Ca2+-sensor properties could lead to cone dysfunction. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Photoreceptor, Neuronal calcium sensor, GCAP, Cone dystrophy
in
Cellular and Molecular Life Sciences1997-01-01+01:00
volume
67
issue
6
pages
973 - 984
publisher
Birkhaüser
external identifiers
  • wos:000274903200011
  • scopus:77949528311
ISSN
1420-9071
DOI
10.1007/s00018-009-0243-8
language
English
LU publication?
yes
id
8ca325e6-3098-4228-9ece-c80af35e2671 (old id 1568311)
date added to LUP
2010-03-23 13:20:07
date last changed
2018-05-29 11:21:02
@article{8ca325e6-3098-4228-9ece-c80af35e2671,
  abstract     = {Guanylate cyclase activating protein 1 (GCAP1) is a neuronal Ca2+ sensor (NCS) that regulates the activation of rod outer segment guanylate cyclases (ROS-GCs) in photoreceptors. In this study, we investigated the Ca2+-induced effects on the conformation and the thermal stability of four GCAP1 variants associated with hereditary human cone dystrophies. Ca2+ binding stabilized the conformation of all the GCAP1 variants independent of myristoylation. The myristoylated wild-type GCAP1 was found to have the highest Ca2+ affinity and thermal stability, whereas all the mutants showed decreased Ca2+ affinity and significantly lower thermal stability in both apo and Ca2+-loaded forms. No apparent cooperativity of Ca2+ binding was detected for any variant. Finally, the nonmyristoylated mutants were still capable of activating ROS-GC1, but the measured cyclase activity was shifted toward high, nonphysiological Ca2+ concentrations. Thus, we conclude that distorted Ca2+-sensor properties could lead to cone dysfunction.},
  author       = {Dell'Orco, Daniele and Behnen, Petra and Linse, Sara and Koch, Karl-Wilhelm},
  issn         = {1420-9071},
  keyword      = {Photoreceptor,Neuronal calcium sensor,GCAP,Cone dystrophy},
  language     = {eng},
  number       = {6},
  pages        = {973--984},
  publisher    = {Birkhaüser},
  series       = {Cellular and Molecular Life Sciences1997-01-01+01:00},
  title        = {Calcium binding, structural stability and guanylate cyclase activation in GCAP1 variants associated with human cone dystrophy},
  url          = {http://dx.doi.org/10.1007/s00018-009-0243-8},
  volume       = {67},
  year         = {2010},
}