title: Structural basis for the Trembler-J phenotype of Charcot-Marie-Tooth disease.
abstract: Mutations in peripheral myelin protein 22 (PMP22) can result in the common peripheral neuropathy Charcot-Marie-Tooth disease (CMTD). The Leu16Pro mutation in PMP22 results in misassembly of the protein, which causes the Trembler-J (TrJ) disease phenotype. Here we elucidate the structural defects present in a partially folded state of TrJ PMP22 that are decisive in promoting CMTD-causing misfolding. In this state, transmembrane helices 2-4 (TM2-4) form a molten globular bundle, while transmembrane helix 1 (TM1) is dissociated from this bundle. The TrJ mutation was seen to profoundly disrupt the TM1 helix, resulting in increased backbone dynamics and changes in the tertiary interactions of TM1 with the PMP22 TM2-4 core in the folded state. Consequently, TM1 undergoes enhanced dissociation from the other transmembrane segments in TrJ PMP22, becoming available for recognition and sequestration by protein-folding quality control, which leads to loss of function and toxic accumulation of aggregates that result in CMTD.
authors.affiliation: Department of Biochemistry, Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-8725, USA.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Sakakura
authors.forename: Arina
authors.initials: A
authors.lastname: Hadziselimovic
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Schey
authors.forename: Charles R
authors.initials: CR
authors.lastname: Sanders
mesh_terms: D000595:Amino Acid Sequence; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002942:Circular Dichroism; D004721:Endoplasmic Reticulum / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009185:Myelin Proteins / Q000737:chemistry* / Q000235:genetics*; D010641:Phenotype; D017510:Protein Folding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D059748:Proteolysis
chemical_list: D009185:Myelin Proteins; C073687:PMP22 protein, human