Innexin Gap Junctions

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Comparison of Inx2 and Zpg/Inx4 protein sequence in the second extracellular domain.

Comparison of Inx2 and Zpg/Inx4 protein sequence in the second extracellular domain.

Innexins, pannexins and connexins all have two extracellular loop domains (E1, E2) containing highly conserved cysteine residues that are involved in hemichannel docking (Bao et al, 2003). The amino acid sequence is shown for Inx2 and Zpg/Inx4 around the region of these conserved cysteine residues (C, red) of the E2 domain (Actually, Zpg/Inx4 is the only innexin to have three cysteine residues in its extracellular loops, but that doesn't seem to impede it from interacting with partners like Inx2). The Inx2TA181 dominant mutant has a glycine to aspartic acid (G to D) substitution within this region and the Inx2UA104 dominant mutant has a serine to phenylalanine (S to F) substitution located only one residue away. Conserved cysteine residues are red, substituted amino acids are green, and other amino acids conserved between Inx2 and Zpg/Inx4 are blue. The zpg allele zpgz-0918 (Tazuke et al, 2002) has a cysteine to tyrosine (C to Y) substitution approx. 9 amino acids away from the sites of the dominant Inx2 mutations. Whether substitutions in the general vicinity of the conserved extracellular cysteine residues can give rise to gain-of –function gap junction subunits is not known but analysis of zpgz-0918 may provide some answers. The dominant Inx2 mutants genetically interact with mutants of sodium pump components and this might be one way of looking for similarities in function of the mutant innexin proteins. Homo- or hemi-zygotes of all three mutants, Inx2TA181, Inx2UA104 and zpgz-0918 produce phenotypes that are indistinguishable from those of inx2null far, anyway. Some dominant connexin mutations are also found in the second extracellular domain (though most published ones are in the first, E1). Substitution of aspartic acid (D, green) by asparagine (N, marked by asterisk) causes a dominant mutation in Cx26 resulting in deafness (Primignani et al, 2003).

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