CLC channels and transporters: proteins with borderline personalities

Abstract

Controlled chloride movement across membranes is essential for a variety of physiological processes ranging from salt homeostasis in the kidneys to acidification of cellular compartments. The CLC family is formed by two, not so distinct, sub-classes of membrane transport proteins: Cl(-) channels and H(+)/Cl(-) exchangers. All CLC's are homodimers with each monomer forming an individual Cl- permeation pathway which appears to be largely unaltered in the two CLC sub-classes. Key residues for ion binding and selectivity are also highly conserved. Most CLC's have large cytosolic carboxy-terminal domains containing two cystathionine beta-synthetase (CBS) domains. The C-termini are critical regulators of protein trafficking and directly modulate Cl- by binding intracellular ATP, H+ or oxidizing compounds. This review focuses on the recent mechanistic insights on the how the structural similarities between CLC channels and transporters translate in unexpected mechanistic analogies between these two sub-classes.

Figure 1

CLC structures. A) The CLC-ec1 dimer is viewed from the plane of the membrane in cartoon representation. Glu_in and Glu_ex are shown in red spacefilling models, Tyr_cen and Ser_cen are shown in yellow spacefilling models. Green spheres represent bound Cl⁻ ions. The green and red dashed lines respectively represent the putative Cl⁻ and H⁺ pathways through CLC-ec1. B) Ribbon representation of the CLC-5 cytoplasmic domain in the ATP bound form. The ATP molecule is shown as a CPK model.