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Molecular basis of hereditary deafness: a theoretical approach

主讲人: Francesco Zonta

时间: 10:00 am, Jan. 30, Friday

地点: Faculty Lounge


Gap junction channels, formed by connexin (Cxs) proteins, are plasma membrane channels which allow the direct communication between the cytoplasm ofjiang adjacent cells. By use of molecular dynamics simulations, we analyzed the effects of two different point mutations of connexin 26 protein, which are linked to hereditary deafness.

The first is a substitution of a methionine with a threonine in the first transmembrane helix of Cx26 (Cx26M34T). Experimental results indicate that channels formed by Cx26M34T retain only 11% of the wild type conductance. Our simulations show that the quaternary structure of the Cx26M34T channel is altered at the level of the pore funnel. As a consequence, the free energy barrier encountered by permeating ions in channels formed by Cx26M34T is significantly higher than in the wild type and thus the unitary conductance is reduced.

The second mutation is given by the substitution of a cysteine with a tyrosine (Cx26C169Y) in the second extracellular loop. The lack of Cys169 disrupts a disulfide bridge, which is fundamental in maintaining the structure of the extra cellular region. As a consequence, the mutant protein shows an alteration in the spatial positioning of two important residues (Asn176 and Thr177), which have been identified as crucial in the intramolecular interactions that keep the structure of the gap junction channels. This theoretical prediction is confirmed by immunofluorencence microscopy experiments showing that CxC169Y proteins do not form gap junction channels in HeLa cells, even though they are correctly targeted to the plasma membrane.



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