Abstract
Protein-folding diseases are an ongoing medical challenge. Many diseases within this group are genetically determined, and have no known cure. Among the examples in which the underlying cellular and molecular mechanisms are well understood are diseases driven by misfolding of transmembrane proteins that normally function as cell-surface ion channels. Wild-type forms are synthesized and integrated into the endoplasmic reticulum (ER) membrane system and, upon correct folding, are trafficked by the secretory pathway to the cell surface. Misfolded mutant forms traffic poorly, if at all, and are instead degraded by the ER-associated proteasomal degradation (ERAD) system. Molecular chaperones can assist the folding of the cytosolic domains of these transmembrane proteins; however, these chaperones are also involved in selecting misfolded forms for ERAD. Given this dual role of chaperones, diseases caused by the misfolding and aberrant trafficking of ion channels (referred to here as ion-channel-misfolding diseases) can be regarded as a consequence of insufficiency of the pro-folding chaperone activity and/or overefficiency of the chaperone ERAD role. An attractive idea is that manipulation of the chaperones might allow increased folding and trafficking of the mutant proteins, and thereby partial restoration of function. This Review outlines the roles of the cytosolic HSP70 chaperone system in the best-studied paradigms of ion-channel-misfolding disease – the CFTR chloride channel in cystic fibrosis and the hERG potassium channel in cardiac long QT syndrome type 2. In addition, other ion channels implicated in ion-channel-misfolding diseases are discussed.
Highlights
Diseases caused by defects in the folding or trafficking of cellsurface ion channels demonstrate how genetic lesions lead to problems at the biochemical and cellular levels, with clinical consequences
Disease Models & Mechanisms (2014) doi:10.1242/dmm.014001. Another model of chaperone involvement in ion-channelmisfolding diseases is provided by congenital long QT syndrome type 2 (LQT2), caused by mutation of a voltage-gated delayed rectifier potassium channel, hERG, known as Kv11.1
CFTR: a paradigm for channel-trafficking defects Folding of CFTR The CFTR ATP-dependent chloride channel is a 1480-residue monomer containing two membrane-spanning domains (MSD1 and MSD2, each with six transmembrane helices) alternating with two cytosolic nucleotide-binding domains, one of which is bound to a regulatory region (NBD1-R and NBD2; Fig. 2) (Mornon et al, 2009)
Summary
Diseases caused by defects in the folding or trafficking of cellsurface ion channels demonstrate how genetic lesions lead to problems at the biochemical and cellular levels, with clinical consequences. The genetic lesion often affects associated domains rather than the active sites of the encoded proteins, causing protein misfolding at the biochemical level, as opposed to loss of ion-channel function per se. As discussed below, how the HSP70 (70 kDa heat shock protein) system relates to CFTR structure and trafficking is still being explored Another model of chaperone involvement in ion-channelmisfolding diseases is provided by congenital long QT syndrome type 2 (LQT2), caused by mutation of a voltage-gated delayed rectifier potassium channel, hERG (human ether-a-go-go-related gene), known as Kv11.1. The most relevant for our discussion is the C-terminus of HSP70interacting protein CHIP (STUB1), which has E3 ubiquitin ligase activity and promotes proteasomal degradation of HSC70- or HSP70-bound substrates
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