1r5s

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Connexin 43 Carboxyl Terminal Domain

Overview

Regulation of cell-cell communication by the gap junction protein, connexin43 can be modulated by a variety of connexin-associating proteins., In particular, c-Src can disrupt the connexin43 (Cx43)-zonula occludens-1, (ZO-1) interaction, leading to down-regulation of gap junction, intercellular communication. The binding sites for ZO-1 and c-Src, correspond to widely separated Cx43 domains (approximately 100 residues, apart); however, little is known about the structural modifications that, may allow information to be transferred over this distance. Here, we have, characterized the structure of the connexin43 carboxyl-terminal domain, (Cx43CT) to assess its ability to interact with domains from ZO-1 and, c-Src. NMR data indicate that the Cx43CT exists primarily as an elongated, random coil, with two regions of alpha-helical structure. NMR titration, experiments determined that the ZO-1 PDZ-2 domain affected the last 19, Cx43CT residues, a region larger than that reported to be required for, Cx43CT-ZO-1 binding. The c-Src SH3 domain affected Cx43CT residues, Lys-264-Lys-287, Ser-306-Glu-316, His-331-Phe-337, Leu-356-Val-359, and, Ala-367-Ser-372. Only region Lys-264-Lys-287 contains the residues, previously reported to act as an SH3 binding domain. The specificity of, these interactions was verified by peptide competition experiments., Finally, we demonstrated that the SH3 domain could partially displace the, Cx43CT-PDZ-2 complex. These studies represent the first structural, characterization of a connexin domain when integrated in a multimolecular, complex. Furthermore, we demonstrate that the structural characteristics, of a disordered Cx43CT are advantageous for signaling between different, binding partners that may be important in describing the mechanism of, channel closure or internalization in response to pathophysiological, stimuli.

About this Structure

1R5S is a Single protein structure of sequence from Rattus norvegicus. Full crystallographic information is available from OCA.

Reference

Structural changes in the carboxyl terminus of the gap junction protein connexin43 indicates signaling between binding domains for c-Src and zonula occludens-1., Sorgen PL, Duffy HS, Sahoo P, Coombs W, Delmar M, Spray DC, J Biol Chem. 2004 Dec 24;279(52):54695-701. Epub 2004 Oct 18. PMID:15492000

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