Pubblicazioni

Autori:

Avesani, Anna; Bielefeld, Laura; Weisschuh, Nicole; Marino, Valerio; Mazzola, Pascale; Stingl, Katarina; Haack, Tobias B; Koch, Karl-Wilhelm; Dell'Orco, Daniele

Titolo:

Molecular properties of human Guanylate Cyclase-Activating Protein 3 (GCAP3) and its possible association with Retinitis Pigmentosa

Anno:

2022

Tipologia prodotto:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Lingua:

Inglese

Formato:

Elettronico

Referee:

Sì

Nome rivista:

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

ISSN Rivista:

1422-0067

N° Volume:

23

Numero o Fascicolo:

3240

Intervallo pagine:

1-21

Parole chiave:

GCAP; GUCA1C; calcium-binding proteins; cyclic GMP; guanylate cyclase (guanylyl cyclase); neurodegenerative disease; phototransduction; retina; retinitis pigmentosa; vision

Breve descrizione dei contenuti:

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.

Note:

Anna Avesani and Laura Bielefeld contributed equally to this work.

Pagina Web:

https://doi.org/10.3390/ijms23063240

Id prodotto:

125594

Handle IRIS:

11562/1061007

ultima modifica:

15 novembre 2022

Citazione bibliografica:

Avesani, Anna; Bielefeld, Laura; Weisschuh, Nicole; Marino, Valerio; Mazzola, Pascale; Stingl, Katarina; Haack, Tobias B; Koch, Karl-Wilhelm; Dell'Orco, Daniele, Molecular properties of human Guanylate Cyclase-Activating Protein 3 (GCAP3) and its possible association with Retinitis Pigmentosa «INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES» , vol. 23 , n. 3240 , 2022 , pp. 1-21

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