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Molecular Properties of Human Guanylate Cyclase-Activating Protein 3 (GCAP3) and Its Possible Association with Retinitis Pigmentosa
- Source :
- International Journal of Molecular Sciences; Volume 23; Issue 6; Pages: 3240
- Publication Year :
- 2022
-
Abstract
- The cone-specific guanylate cyclase-activating protein 3 (GCAP3), encoded by the GUCA1C gene, has been shown to regulate the enzymatic activity of membrane-bound guanylate cyclases (GCs) in bovine and teleost fish photoreceptors, to an extent comparable to that of the paralog protein GCAP1. To date, the molecular mechanisms underlying GCAP3 function remain largely unexplored. In this work, we report a thorough characterization of the biochemical and biophysical properties of human GCAP3, moreover, we identified an isolated case of retinitis pigmentosa, in which a patient carried the c.301G>C mutation in GUCA1C, resulting in the substitution of a highly conserved aspartate residue by a histidine (p.(D101H)). We found that myristoylated GCAP3 can activate GC1 with a similar Ca2+-dependent profile, but significantly less efficiently than GCAP1. The non-myristoylated form did not induce appreciable regulation of GC1, nor did the p.D101H variant. GCAP3 forms dimers under physiological conditions, but at odds with its paralogs, it tends to form temperature-dependent aggregates driven by hydrophobic interactions. The peculiar properties of GCAP3 were confirmed by 2 ms molecular dynamics simulations, which for the p.D101H variant highlighted a very high structural flexibility and a clear tendency to lose the binding of a Ca2+ ion to EF3. Overall, our data show that GCAP3 has unusual biochemical properties, which make the protein significantly different from GCAP1 and GCAP2. Moreover, the newly identified point mutation resulting in a substantially unfunctional protein could trigger retinitis pigmentosa through a currently unknown mechanism.
- Subjects :
- retina
vision
phototransduction
guanylate cyclase (guanylyl cyclase)
cyclic GMP
calcium-binding proteins
retinitis pigmentosa
neurodegenerative disease
GUCA1C
GCAP
Catalysis
Inorganic Chemistry
Animals
Humans
Physical and Theoretical Chemistry
Molecular Biology
Spectroscopy
Organic Chemistry
Calcium-Binding Proteins
General Medicine
Guanylate Cyclase-Activating Proteins
Computer Science Applications
Guanylate Cyclase
Retinal Cone Photoreceptor Cells
Calcium
Cattle
Retinitis Pigmentosa
Subjects
Details
- ISSN :
- 14220067
- Volume :
- 23
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- International journal of molecular sciences
- Accession number :
- edsair.doi.dedup.....3e783160d3a4f18c8024ffd978fde63a