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1 Zentrum für Molekulare Neurobiologie Hamburg (ZMNH), Hamburg University, Falkenried 94, D-20246 Hamburg, Germany2 Istituto di Biofisica, Via de Marini 6, I-16149 Genova, Italy3 Departament de Bioquímica i Biología Molecular, Facultat de Quimica, Universitat de Barcelona, Marti i Franques 1, Barcelona 08028, and Institut de Recerca Biomédica, Parc Científic de Barcelona, Josep Samitier 1–5, Barcelona 08028, Spain
All eukaryotic CLC Cl– channel subunits possess a long cytoplasmic carboxy-terminus that contains two so-called CBS (cystathionine ß-synthase) domains. These domains are found in various unrelated proteins from all phylae. The crystal structure of the CBS domains of inosine monophosphate dehydrogenase (IMPDH) is known, but it is not known whether this structure is conserved in CLC channels. Working primarily with ClC-1, we used deletion scanning mutagenesis, coimmunoprecipitation and electrophysiology to demonstrate that its CBS domains interact. The replacement of CBS domains of ClC-1 with the corresponding CBS domains from other CLC channels and even human IMPDH yielded functional channels, indicating a high degree of structural conservation. Based on a homology model of the pair of CBS domains of CLC channels, we identified some residues that, when mutated, affected the common gate which acts on both pores of the dimeric channel. Thus, we propose that the structure of CBS domains from CLC channels is highly conserved and that they play a functional role in the common gate.
(Received 20 November 2003;
accepted after revision 5 January 2004;
first published online 14 January 2004)
Corresponding author T. J. Jeutsch: Zentrum für Molekulare Neurobiologie Hamburg (ZMNH), Hamburg University, Falkenried 94, D-20246 Hamburg, Germany. Email: jentsch{at}zmnh.uni-hamburg.de
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