Ion mobility–mass spectrometry reveals the role of peripheral myelin protein dimers in peripheral neuropathy

Peripheral myelin protein (PMP22) is an integral membrane protein that traffics inefficiently even in wild-type (WT) form, with only 20% of the WT protein reaching its final plasma membrane destination in myelinating Schwann cells. Misfolding of PMP22 has been identified as a key factor in multiple...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-04, Vol.118 (17), p.1-8
Main Authors: Fantin, Sarah M., Parson, Kristine F., Yadav, Pramod, Juliano, Brock, Li, Geoffrey C., Sanders, Charles R., Ohi, Melanie D., Ruotolo, Brandon T.
Format: Article
Language:English
Subjects:
Abundance
Biological Sciences
Charcot-Marie-Tooth disease
Destabilization
Dimers
Ionic mobility
Lipids
Mass spectrometry
Mass spectroscopy
Membrane proteins
Membranes
Micelles
Mimicry
Mobility
Monomers
Mutants
Mutation
Myelin
Peripheral myelin protein 22
Peripheral neuropathy
Physical Sciences
Protein folding
Proteins
Schwann cells
Scientific imaging
Spectroscopy
Vapor phases
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Summary:Peripheral myelin protein (PMP22) is an integral membrane protein that traffics inefficiently even in wild-type (WT) form, with only 20% of the WT protein reaching its final plasma membrane destination in myelinating Schwann cells. Misfolding of PMP22 has been identified as a key factor in multiple peripheral neuropathies, including Charcot-Marie-Tooth disease and Dejerine–Sottas syndrome. While biophysical analyses of disease-associated PMP22 mutants show altered protein stabilities, leading to reduced surface trafficking and loss of PMP22 function, it remains unclear how destabilization of PMP22 mutations causes mistrafficking. Here, native ion mobility–mass spectrometry (IM-MS) is used to compare the gas phase stabilities and abundances for an array of mutant PM22 complexes. We find key differences in the PMP22 mutant stabilities and propensities to form homodimeric complexes. Of particular note, we observe that severely destabilized forms of PMP22 exhibit a higher propensity to dimerize than WT PMP22. Furthermore, we employ lipid raft–mimicking SCOR bicelles to study PMP22 mutants, and find that the differences in dimer abundances are amplified in this medium when compared to micellebased data, with disease mutants exhibiting up to 4 times more dimer than WT when liberated from SCOR bicelles. We combine our findings with previous cellular data to propose that the formation of PMP22 dimers from destabilized monomers is a key element of PMP22 mistrafficking.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2015331118