The CNG channel is arranged as a dimer of dimers
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The domains that 'hang' below the transmembrane part of the CNG channel are arranged as two regions of density, related to one another by approximate two-fold symmetry. This change from an approximate four-fold to two-fold symmetry is seen clearly in cross-sections of the channel (Figure 4F-I). We propose that each of these smaller domains contain a dimer of ligand binding domains. However, as the resolution obtained does not allow us to distinguish between the a- and b-subunits of the channel we are unable to say whether these two dimers are formed from the ligand-binding domains of like subunits and the channel is a dimer of a-subunits and a dimer of b-subunits, or whether another arrangement of subunits is adopted. Although the structure presented here is the first view of an intact CNG channel, the idea that the cyclic nucleotide-binding domains of the channel are arranged as a pair of dimers is not new. The structure of a chimera of the CNG channel cyclic nucleotide-binding domain fused to the DNA binding domain of CAP (Scott et al., 2001) shows the ligand-binding domain to form a dimer. This is also the case in the homologous cyclic nucleotide-binding domain of CAP (Weber and Steitz, 1987). The gating properties of CNG channels also indicate that the subunits are arranged as two functional dimers (Liu et al., 1998). The conductance properties of channels that have been constrained to have different ligand occupancies are consistent with a model in which subunits function together as pairs. Within each pair of subunits, the gating transition occurs in a cooperative manner. However, the two pairs of subunits go through the gating transition independently. This is similar to the CAP, in which the two subunits of the dimer display cooperativity (Takahashi et al., 1980). The CNG channels are not alone as tetrameric channels that have two pairs of dimeric ligand binding domains arranged in the cytoplasm. Recent structures of the gating domains of the small and large conductance calcium-activated potassium channels at atomic resolution also show ligand binding domains that fold as dimers (Jiang et al., 2001; Schumacher et al., 2001). Whether these features are common to ion channels that are gated by the binding of intracellular ligands, and what the consequences of this arrangement are for the high-resolution structure and the function of the channel as a whole, remain to be investigated. |
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