Conformational Stability and Pathogenic Misfolding of the Integral Membrane Protein PMP22.

Schlebach JP, Narayan M, Alford C, Mittendorf KF, Carter BD, Li J, Sanders CR
J Am Chem Soc. 2015 137 (27): 8758-68

PMID: 26102530 · PMCID: PMC4507940 · DOI:10.1021/jacs.5b03743

Despite broad biochemical relevance, our understanding of the physiochemical reactions that limit the assembly and cellular trafficking of integral membrane proteins remains superficial. In this work, we report the first experimental assessment of the relationship between the conformational stability of a eukaryotic membrane protein and the degree to which it is retained by cellular quality control in the secretory pathway. We quantitatively assessed both the conformational equilibrium and cellular trafficking of 12 variants of the α-helical membrane protein peripheral myelin protein 22 (PMP22), the intracellular misfolding of which is known to cause peripheral neuropathies associated with Charcot-Marie-Tooth disease (CMT). We show that the extent to which these mutations influence the energetics of Zn(II)-mediated PMP22 folding is proportional to the observed reduction in cellular trafficking efficiency. Strikingly, quantitative analyses also reveal that the reduction of motor nerve conduction velocities in affected patients is proportional to the extent of the mutagenic destabilization. This finding provides compelling evidence that the effects of these mutations on the energetics of PMP22 folding lie at the heart of the molecular basis of CMT. These findings highlight conformational stability as a key factor governing membrane protein biogenesis and suggest novel therapeutic strategies for CMT.

MeSH Terms (17)

Amino Acid Sequence Animals Charcot-Marie-Tooth Disease Dogs Humans Madin Darby Canine Kidney Cells Metals Models, Molecular Molecular Sequence Data Mutation, Missense Myelin Proteins Peripheral Nervous System Diseases Protein Conformation Protein Folding Protein Stability Protein Transport Thermodynamics

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