Misalignment of PLP/DM20 transmembrane domains determines protein misfolding in Pelizaeus-Merzbacher disease.
A large number of genetic diseases have been associated with truncated or misfolded membrane proteins trapped in the endoplasmic reticulum (ER). In the ER, they activate the unfolded protein response, which can trigger cell death. Hence, a better understanding of protein misfolding features might help in developing novel therapies. Here, we have studied the molecular basis of Pelizaeus-Merzbacher disease, a leukodystrophy defined by mutations of the PLP1 gene and ER retention of two encoded tetraspan myelin proteins, PLP and DM20. In mouse oligodendroglial cells, mutant isoforms of PLP/DM20 with fewer than all four transmembrane (TM) domains are fully ER retained. Surprisingly, a truncated PLP with only two N-terminal TM domains shows normal cell-surface expression when coexpressed with a second truncated PLP harboring the two C-terminal TM domains. This striking ability to properly self-align the TM domains is disease relevant, as shown for the smaller splice isoform DM20. Here, the increased length of TM domain 3 allows for compensation of the effect of several PLP1 point mutations that impose a conformational constraint onto the adjacent extracellular loop region. We conclude that an important determinant in the quality control of polytopic membrane proteins is the free alignment of their TM domains.
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, D-37075 Göttingen, Germany. ajit.dhaunchak@mcgill.ca
Ajit Singh
AS
Dhaunchak
David R
DR
Colman
Klaus-Armin
KA
Nave
D000818:Animals; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D014162:Transfection
D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins