PMP22 associates with MPZ via their transmembrane domains and disrupting this interaction causes a loss-of-function phenotype similar to hereditary neuropathy associated with liability to pressure palsies (HNPP)

Abstract

PMP22 and MPZ are major myelin proteins in the peripheral nervous system. MPZ is a single pass integral membrane protein with an extracellular immunoglobulin (Ig)-like domain and works as an adhesion protein to hold myelin wraps together across the intraperiod line. Loss of MPZ causes severe demyelinating Charcot-Marie-Tooth (CMT) peripheral neuropathy. PMP22 is an integral membrane tetraspan protein belonging to the Claudin superfamily. Homozygous loss of PMP22 also leads to severe demyelinating neuropathy, and duplication of wildtype 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 that these abundant myelin proteins form a strong and specific complex. Mutagenesis and domain swapping experiments reveal that these proteins interact through interfaces within their transmembrane domains. We also find that the PMP22 A67T patient variant that causes an HNPP (Hereditary neuropathy with pressure palsies) phenotype, reflecting a heterozygous loss-of-function, maps to this interface. The PMP22 A67T variant results in the specific loss of MPZ association with PMP22 without affecting PMP22 localization to the plasma membrane or its interactions with other proteins. These data define the molecular basis for the MPZ∼PMP22 interaction and indicate that the MPZ∼PMP22 complex fulfills an important function in myelinating cells.