Publications

Authors:

Avesani, Anna; Marino, Valerio; Zanzoni, Serena; Koch, Karl-Wilhelm; Dell'Orco, Daniele

Title:

Molecular properties of human guanylate cyclase-activating protein 2 (GCAP2) and its retinal dystrophy-associated variant G157R

Year:

2021

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Format:

Elettronico

Referee:

Sì

Name of journal:

JBC

ISSN of journal:

0021-9258

N° Volume:

296

Number or Folder:

100619

Page numbers:

1-17

Keyword:

GCAP; GUCA1B; calcium-binding proteins; cyclic GMP (cGMP); guanylate cyclase (guanylyl cyclase); neurodegenerative disease; phototransduction; retina; retinal degeneration; vision

Short description of contents:

In murine and bovine photoreceptors, guanylate cyclase activating-protein 2 (GCAP2) activates retinal guanylate cyclases (GC) at low Ca2+ levels, thus contributing to the Ca2+/cGMP negative feedback on the cyclase together with its paralog GCAP1, which has the same function but different Ca2+ sensitivity. In humans, a GCAP2 missense mutation (G157R) has been associated with inherited-retinal degeneration (IRD) via an unknown molecular mechanism. Here, we characterized the biochemical properties of human GCAP2 and the G157R variant, focusing on its dimerization and the Ca2+/Mg2+-binding processes in the presence or absence of N-terminal myristoylation. We found that human GCAP2 and its bovine/murine orthologs significantly differ in terms of oligomeric properties, cation binding, and GC regulation. Myristoylated GCAP2 endothermically binds up to three Mg2+ ions with high affinity and forms a compact dimer that may reversibly dissociate in the presence of Ca2+. Conversely, non-myristoylated GCAP2 does not bind Mg2+ over the physiological range, and remains as a monomer in the absence of Ca2+. Both myristoylated and non-myristoylated GCAP2 bind Ca2+ with high affinity. At odds with GCAP1 and independently of myristoylation, human GCAP2 does not significantly activate retinal GC1 in a Ca2+-dependent fashion. The IRD-associated G157R variant is characterized by a partly misfolded, molten globule-like conformation with reduced affinity for cations, and is prone to form aggregates, likely mediated by hydrophobic interactions. Our findings suggest that GCAP2 in human photoreceptors might be mostly implicated in processes other than phototransduction, and suggest a possible molecular mechanism for G157R-associated IRD.

Web page:

https://doi.org/10.1016/j.jbc.2021.100619

Product ID:

120692

Handle IRIS:

11562/1041471

Last Modified:

November 9, 2022

Bibliographic citation:

Avesani, Anna; Marino, Valerio; Zanzoni, Serena; Koch, Karl-Wilhelm; Dell'Orco, Daniele, Molecular properties of human guanylate cyclase-activating protein 2 (GCAP2) and its retinal dystrophy-associated variant G157R «JBC» , vol. 296 , n. 100619 , 2021 , pp. 1-17

Consulta la scheda completa presente nel repository istituzionale della Ricerca di Ateneo