Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:6.2.1.1 (
ACS
)
78,556
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Shaping the temporal response of photoreceptors is facilitated by a well-balanced second messenger cascade, in which two neuronal Ca(2+)-sensor proteins operate in a sequential relay mechanism. Although they share structurally similar sensing units, they differentially activate the same target protein. Here, as a prototypical case in Ca(2+)-mediated signal processing, we investigate differential cellular responsiveness in protein conformational dynamics on a nanosecond time scale. For this, we have site-specifically labeled cysteine residues in guanylate cyclase-activating protein
GCAP1
by the fluorescent dye Alexa647 and probed its local environment via time-resolved fluorescence spectroscopy. Fluorescence lifetime and rotational anisotropy measurements reveal a distinct structural movement of the polypeptide chain around position 106 upon release of Ca(2+). This is supported by analyzing the diffusional dye motion in a wobbling-in-a-cone model and by molecular dynamics simulations. We conclude that
GCAP1
and its cellular cognate GCAP2 operate by distinctly different switching mechanisms despite their high structural homology.
ACS
Chem Biol 2015 Oct 16
PMID:Differential Nanosecond Protein Dynamics in Homologous Calcium Sensors. 2620 33
Genetic heterogeneity leading to retinal disorders impairs biological processes by causing, for example, severe disorder of signal transduction in photoreceptor outer segments. A normal balance of the second messenger homeostasis in photoreceptor cells seems to be a crucial factor for healthy and normal photoreceptor function. Genes like
GUCY2D
coding for guanylate cyclase GC-E and
GUCA1A
coding for the Ca
2+
-sensor guanylate cyclase-activating protein
GCAP1
are critical for a precisely controlled synthesis of the second messenger cGMP. Mutations in
GUCA1A
frequently correlate in patients with cone dystrophy and cone-rod dystrophy. Here, we report two mutations in the
GUCA1A
gene that were found in patients diagnosed with retinitis pigmentosa, a phenotype that was rarely detected among previous cases of
GUCA1A
related retinopathies. One patient was heterozygous for the missense variant c.55C > T (p.H19Y), while the other patient was heterozygous for the missense variant c.479T > G (p.V160G). Using heterologous expression and cell culture systems, we examined the functional and molecular consequences of these point mutations. Both variants showed a dysregulation of guanylate cyclase activity, either a profound shift in Ca
2+
-sensitivity (H19Y) or a nearly complete loss of activating potency (V160G). Functional heterogeneity became also apparent in Ca
2+
/Mg
2+
-binding properties and protein conformational dynamics. A faster progression of retinal dystrophy in the patient carrying the V160G mutation seems to correlate with the more severe impairment of this variant.
ACS
Chem Neurosci 2020 05 20
PMID:Neuronal Calcium Sensor GCAP1 Encoded by
GUCA1A
Exhibits Heterogeneous Functional Properties in Two Cases of Retinitis Pigmentosa. 3229 85
