To identify signals that convey connexin oligomerization compatibility, we have aligned amino-acid sequences of α and β group connexins (Cx)and compared the physico-chemical properties of each homologous amino-acid residue. Four positions were identified that consistently differed betweenα and β-type connexins; two are located in the N-terminal domain(P1 and P2, corresponding to residues 12 and 13 of the Cx43 sequence), and two in the third trans-membrane-spanning domain TM3 (P3 and P4, corresponding to residues 152 and 153 of the Cx43 sequence). Replacement of each of these residues in Cx43 (an α-type connexin) with the corresponding residues of Cx32 (a β-type connexin) resulted in the assembly of all variants into gap junctions; however, only the P4 variant was functional, as indicated by lucifer yellow dye transfer assays. The other three variants exerted a moderate to severe dose-dependent, dominant-negative effect on co-expressed wild-type (wt) Cx43 channel activity. Moreover, a significant dose-dependent,trans-dominant inhibition of channel activity was observed when either one of the N-terminal variants was co-expressed with wt Cx32. Assembly analyses indicated that dominant and trans-dominant inhibitory effects appeared to be based on the oligomerization of wt and variant connexins into mixed connexons. Interestingly, the identified N-terminal amino acids coincide with the position of naturally occurring, disease-causing missense mutations of severalβ-connexin genes (Cx26, Cx30, Cx31, Cx32). Our results demonstrate that three of the identified discriminative amino-acid residues(positions 12, 13 and 152) are crucial for Cx43 channel function and suggest that the N-terminal amino-acid residues at position 12/13 are involved in the oligomerization compatibility of α and β connexins.
Specific amino-acid residues in the N-terminus and TM3 implicated in channel function and oligomerization compatibility of connexin43 Available to Purchase
Present address: Université de Bordeaux I, Pôle Biologie Cellulaire et Moléculaire, Institut Européen de Chimie et Biologie, Avenue des Facultés, 33405 Talence Cedex, France
Present address: Department of Biology, University of Fribourg, Perolles,Ch-1700 Fribourg, Switzerland
Deceased September 2000
Valérie Lagrée, Karin Brunschwig, Patricia Lopez, Norton B. Gilula, Gabriele Richard, Matthias M. Falk; Specific amino-acid residues in the N-terminus and TM3 implicated in channel function and oligomerization compatibility of connexin43. J Cell Sci 1 August 2003; 116 (15): 3189–3201. doi: https://doi.org/10.1242/jcs.00604
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