Conformational Stability and Pathogenic Misfolding of the Integral Membrane Protein PMP22

Area of Science:

• Biochemistry
• Cell Biology
• Neuroscience

Background:

• Integral membrane protein assembly and trafficking are crucial but poorly understood.
• Intracellular misfolding of peripheral myelin protein 22 (PMP22) causes peripheral neuropathies in Charcot-Marie-Tooth disease (CMT).

Purpose of the Study:

• To experimentally assess the link between conformational stability of PMP22 variants and their quality control retention in the secretory pathway.
• To investigate the molecular basis of CMT by correlating PMP22 folding energetics with disease phenotypes.

Main Methods:

• Quantitative assessment of conformational equilibrium for 12 PMP22 variants.
• Measurement of cellular trafficking efficiency of PMP22 variants in the secretory pathway.
• Analysis of the relationship between mutation-induced changes in folding energetics and trafficking defects.

Main Results:

• The degree of PMP22 misfolding and reduced cellular trafficking efficiency is proportional to how mutations affect the energetics of Zn(II)-mediated folding.
• Reduction in motor nerve conduction velocities in CMT patients is directly proportional to the extent of PMP22 destabilization caused by mutations.
• Conformational stability is a critical determinant of PMP22 biogenesis and trafficking.

Conclusions:

• The energetics of PMP22 folding are central to the molecular pathogenesis of CMT.
• Conformational stability is a key factor in membrane protein biogenesis.
• These findings suggest novel therapeutic strategies for CMT targeting protein folding and stability.