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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 Sciences 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
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Photoreceptor, Neuronal calcium sensor, GCAP, Cone dystrophy
in
Cellular and Molecular Life Sciences
volume
67
issue
6
pages
973 - 984
publisher
Birkhäuser Verlag
external identifiers
  • wos:000274903200011
  • scopus:77949528311
  • pmid:20213926
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
2016-04-01 14:12:16
date last changed
2022-05-07 21:36:37
@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}},
  keywords     = {{Photoreceptor; Neuronal calcium sensor; GCAP; Cone dystrophy}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{973--984}},
  publisher    = {{Birkhäuser Verlag}},
  series       = {{Cellular and Molecular Life Sciences}},
  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}},
  doi          = {{10.1007/s00018-009-0243-8}},
  volume       = {{67}},
  year         = {{2010}},
}