Preferential Binding of Mg2+ Over Ca2+ to CIB2 Triggers an Allosteric Switch Impaired in Usher Syndrome Type 1J

Frontiers in Molecular Neuroscience
Rosario ValloneDaniele Dell'Orco

Abstract

Calcium and integrin binding protein 2 (CIB2) shares with the other members of the CIB family the ability to bind Ca2+ and Mg2+ via two functional EF-hand motifs, namely EF3 and EF4. As a cation sensor, CIB2 is able to switch to a conformation likely associated with specific biological functions yet to be clarified. Recent findings demonstrate the involvement of CIB2 in hearing physiology and a single, conservative point mutation (p.E64D) has been related to Usher Syndrome type 1J (USH1J) and non-syndromic hearing loss. We present an exhaustive biochemical and biophysical characterization of human wild type (WT) and E64D CIB2. We found that CIB2 does not possibly work as a calcium sensor under physiological conditions, its affinity for Ca2+ (Kdapp = 0.5 mM) being too low for detecting normal intracellular levels. Instead, CIB2 displays a significantly high affinity for Mg2+ (Kdapp = 290 μM), and it is probably Mg2+ -bound under physiological conditions. At odds with the homologous protein CIB1, CIB2 forms a non-covalent dimer under conditions that mimic the physiological ones, and as such it interacts with its physiological target α7B integrin. NMR spectroscopy revealed a long-range allosteric communication between the residue ...Continue Reading

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Citations

May 7, 2020·Ophthalmic Genetics·Rosalie M NolenWadih M Zein
Mar 23, 2019·Frontiers in Molecular Neuroscience·Valerio Marino, Daniele Dell'Orco
Nov 17, 2020·Frontiers in Genetics·Meg WhatleyElaine Y M Wong
Jun 25, 2021·Nature Communications·Saumil SethnaZubair M Ahmed
Jul 11, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Giuditta Dal CortivoDaniele Dell'Orco

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Methods Mentioned

BETA
NMR
size exclusion chromatography
electrophoresis
X-ray
fluorescence spectroscopy
Fluorescence

Software Mentioned

MODBASE
MaxChelator
GraphPad
MODWEB
TOPSPIN
CARA

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