Understanding the molecular basis of the functional defects in CIB2 related to Usher syndrome type 1J
Calcium- and integrin- binding protein 2 (CIB2) is a calcium sensor recently found to be involved in Usher syndrome J1 (USH1J), a severe disease leading to profound congenital hearing impairment and adolescent-onset blindness. Protein localization in both mechanosensory stereocilia of the inner ear hair, retinal photoreceptors inner and outer segments and pigmented epithelium cells suggest as a common feature of molecular dysfunction an impairment of the calcium homeostasis. However, dedicated mechanistic studies and even basic biochemical characterization of the identified pathological CIB2 variants are currently missing. The project aims at setting the basis for understanding the molecular mechanisms underlying the dysfunctional forms of CIB2. In particular, we will charatcerize both wild type CIB2 and the p.E64D and variant associated to USH1J.
- Clarify whether the effect of the mutation is mostly to alter the structural/functional features of CIB2 and its integrin partner
- Probe the capability of CIB2 variants to physiologically bind Ca2+
- Measure both affinity and kinetics of the interaction with integrin peptides, in order to uncover potential hallmarks of disease at a molecular level.
- Run Molecular Dynamics simulations to highlight the determinants of the interactions at atomistic level.