The Folding Pathway of ABC Transporter CFTR: Effective and Robust.

[Display omitted] • CFTR attains function through temporally overlapping co-translational domain folding and post-translational domain assembly stages, which ensures an effective and robust folding process. • Most missense mutations in CF patients affect domain assembly, the stage that is rescued by modulators. • Transmembrane helices 7 and 8 constitute an aggregation-prone determinant in CFTR. • Effects of modulators on CFTR folding or conformation can be uncovered in folding assays in cells. • Low-temperature rescues CFTR domain assembly but not NBD1 folding. • Factors affecting a domain's folding are distinct from factors affecting that same domain's stability. De novo protein folding into a native three-dimensional structure is indispensable for biological function, is instructed by its amino acid sequence, and occurs along a vectorial trajectory. The human proteome contains thousands of membrane-spanning proteins, whose biosynthesis begins on endoplasmic reticulum-associated ribosomes. Nearly half of all membrane proteins traverse the membrane more than once, including therapeutically important protein families such as solute carriers, G-protein-coupled receptors, and ABC transporters. These mediate a variety of functions like signal transduction and solute transport and are often of vital importance for cell function and tissue homeostasis. Missense mutations in multispan membrane proteins can lead to misfolding and cause disease; an example is the ABC transporter Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Even though our understanding of multispan membrane-protein folding still is rather rudimental, the cumulative knowledge of 20 years of basic research on CFTR folding has led to development of drugs that modulate the misfolded protein. This has provided the prospect of a life without CF to the vast majority of patients. In this review we describe our understanding of the folding pathway of CFTR in cells, which is modular and tolerates many defects, making it effective and robust. We address how modulator drugs affect folding and function of CFTR, and distinguish protein stability from its folding process. Since the domain architecture of (mammalian) ABC transporters are highly conserved, we anticipate that the insights we discuss here for folding of CFTR may lay the groundwork for understanding the general rules of ABC-transporter folding. [ABSTRACT FROM AUTHOR]