# Allosteric Communication of the Dimerization and the Catalytic Domain in Photoreceptor Guanylate Cyclase

## TL;DR

This study explores how calcium ions regulate the activity of a key enzyme in vision, revealing an allosteric communication pathway between distant parts of the enzyme.

## Contribution

The paper identifies a novel allosteric communication mechanism in GC-E involving conserved amino acid positions.

## Key findings

- Ca2+ inhibits the V902L mutant of GC-E by replacing Mg2+ in the catalytic center.
- Mutation at position 804 reduces catalytic efficiency without affecting the main activation mechanism.
- Allosteric communication connects the α-helical and catalytic domains in GC-E.

## Abstract

Phototransduction
in vertebrate photoreceptor cells is controlled
by Ca2+-dependent feedback loops involving the membrane-bound
guanylate cyclase GC-E that synthesizes the second messenger guanosine-3′,5′-cyclic
monophosphate. Intracellular Ca2+-sensor proteins named
guanylate cyclase-activating proteins (GCAPs) regulate the activity
of GC-E by switching from a Ca2+-bound inhibiting state
to a Ca2+-free/Mg2+-bound activating state.
The gene GUCY2D encodes for human GC-E, and mutations
in GUCY2D are often associated with an imbalance
of Ca2+ and cGMP homeostasis causing retinal disorders.
Here, we investigate the Ca2+-dependent inhibition of the
constitutively active GC-E mutant V902L. The inhibition is not mediated
by GCAP variants but by Ca2+ replacing Mg2+ in
the catalytic center. Distant from the cyclase catalytic domain is
an α-helical domain containing a highly conserved helix-turn-helix
motif. Mutating the critical amino acid position 804 from leucine
to proline left the principal activation mechanism intact but resulted
in a lower level of catalytic efficiency. Our experimental analysis
of amino acid positions in two distant GC-E domains implied an allosteric
communication pathway connecting the α-helical and the cyclase
catalytic domains. A computational connectivity analysis unveiled
critical differences between wildtype GC-E and the mutant V902L in
the allosteric network of critical amino acid positions.