Journal article
Disrupting the transmembrane domain interface between PMP22 and MPZ causes peripheral neuropathy
iScience, Vol.27(11), 110989
11/2024
DOI: 10.1016/j.isci.2024.110989
PMCID: PMC11700639
PMID: 39759075
Abstract
PMP22 and MPZ are abundant myelin membrane proteins in Schwann cells. The MPZ adhesion protein holds myelin wraps together across the intraperiod line. PMP22 is a tetraspan protein belonging to the Claudin superfamily. Loss of either MPZ or PMP22 causes severe demyelinating Charcot-Marie-Tooth (CMT) peripheral neuropathy, and duplication of PMP22 causes the most common form of CMT, CMT1A. Yet, the molecular functions provided by PMP22 and how its alteration causes CMT are unknown. Here we find MPZ and PMP22 form a specific complex through interfaces within their transmembrane domains. We also find that the PMP22 A67T patient variant that causes a loss-of-function (Hereditary Neuropathy with Pressure Palsies) phenotype maps to this interface, and blocks MPZ association without affecting localization to the plasma membrane or interactions with other proteins. These data define the molecular basis for the MPZ∼PMP22 interaction and indicate this complex fulfills an important function in myelinating cells.
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•MPZ and PMP22 form a complex, through their transmembrane domains•A loss-of-function PMP22 variant blocks MPZ association.•Blocking MPZ association has no effect on trafficking or other PMP22 interactions
Details
- Title: Subtitle
- Disrupting the transmembrane domain interface between PMP22 and MPZ causes peripheral neuropathy
- Creators
- Natalya Pashkova - University of IowaTabitha A. Peterson - University of IowaChristopher P. Ptak - University of IowaStanley C. Winistorfer - University of IowaDebbie Guerrero-Given - Max Planck Florida Institute for NeuroscienceNaomi Kamasawa - Max Planck Florida Institute for NeuroscienceChristopher A. Ahern - University of IowaMichael E. Shy - University of IowaRobert C. Piper - Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City 52242
- Resource Type
- Journal article
- Publication Details
- iScience, Vol.27(11), 110989
- DOI
- 10.1016/j.isci.2024.110989
- PMID
- 39759075
- PMCID
- PMC11700639
- NLM abbreviation
- iScience
- ISSN
- 2589-0042
- eISSN
- 2589-0042
- Publisher
- Elsevier Inc
- Grant note
- NIH: RO1GM058202
We acknowledge the University of Iowa personnel and instrumentation in the IIHG Genomic Sequencing, the Carver College of Medicine NMR, and Protein & Crystallography core facilities, supported by the Roy J. and Lucille A. Carver College of Medicine and grants from the Roy J. Carver Charitable Trust. We thank Miranda Schene and Sandipan Chowdhury for help with detergent and FPLC analysis. This work was supported by NIH-R01 GM106568 to C.A.A., U54NS065712 to M.E.S., and NIH RO1GM058202 to R.C.P. C.A.A. and R.C.P. were supported by the Roy J. Carver Charitable Trust.
- Language
- English
- Electronic publication date
- 09/2024
- Date published
- 11/2024
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Medicine Administration; Internal Medicine
- Record Identifier
- 9984719244702771
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