Publications

Authors:

Biasi, Amedeo; Marino, Valerio; Dal Cortivo, Giuditta; Dell'Orco, Daniele

Title:

Supramolecular complexes of GCAP1: implications for inherited retinal dystrophies

Year:

2024

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Format:

Elettronico

Referee:

Sì

Name of journal:

INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES

ISSN of journal:

0141-8130

N° Volume:

279

Number or Folder:

Pt 1

:

-Attuale :ELSEVIER SCIENCE BV, PO BOX 211, AMSTERDAM, NETHERLANDS, 1000 AE -Butterworth Heinemann Publishers:Linacre House Jordan Hill, Oxford OX2 8DP United Kingdom:011 44 1865 314569, EMAIL: bhmarketing@repp.co.uk, INTERNET: http://www.laxtonsprices.co.uk, Fax: 011 44 1865 314569

Page numbers:

1-12

Keyword:

Biologics; Guanylate cyclase; RD3

Short description of contents:

Guanylate Cyclase Activating Protein 1 (GCAP1) is a calcium sensor that regulates the enzymatic activity of retinal Guanylate Cyclase 1 (GC1) in photoreceptors in a Ca2+/Mg2+ dependent manner. While point mutations in GCAP1 have been associated with inherited retinal dystrophies (IRDs), their impact on protein dimerization or on the possible interaction with the potent GC1 inhibitor RD3 (retinal degeneration protein 3) has never been investigated. Here, we integrate exhaustive in silico investigations with biochemical assays to evaluate the effects of the p.(E111V) substitution, associated with a severe form of IRD, on GCAP1 homo- and hetero-dimerization, and demonstrate that wild type (WT) GCAP1 directly interacts with RD3. Although inducing constitutive activation in GC1, the E111V substitution only slightly affects the dimerization of GCAP1. Both WT- and E111V-GCAP1 are predominantly monomeric in the absence of the GC1 target, however E111V-GCAP1 shows a stronger tendency to be monomeric in the Ca2+-bound form, corresponding to GC1 inhibiting state. Reconstitution experiments performed in the co-presence of WT-GCAP1, E111V-GCAP1 and RD3 restored nearly physiological regulation of the GC1 enzymatic activity in terms of cGMP synthesis and Ca2+-sensitivity, suggesting new scenarios for biologics-mediated treatment of GCAP1-associated IRDs.

Web page:

https://doi.org/10.1016/j.ijbiomac.2024.135068

Product ID:

141310

Handle IRIS:

11562/1139526

Last Modified:

October 3, 2024

Bibliographic citation:

Biasi, Amedeo; Marino, Valerio; Dal Cortivo, Giuditta; Dell'Orco, Daniele, Supramolecular complexes of GCAP1: implications for inherited retinal dystrophies «INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES» , vol. 279 , n. Pt 1 , 2024 , pp. 1-12

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