Proteolipid protein dimerization at cysteine 108: Implications for protein structure

Gurdip Daffu; Jasloveleen Sohi; John Kamholz

doi:10.1016/j.neures.2012.07.009

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Proteolipid protein dimerization at cysteine 108: Implications for protein structure

Journal article

Peer reviewed

Proteolipid protein dimerization at cysteine 108: Implications for protein structure

Gurdip Daffu, Jasloveleen Sohi and John Kamholz

Neuroscience research, Vol.74(2), pp.144-155

10/2012

DOI: 10.1016/j.neures.2012.07.009

PMID: 22902553

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Abstract

Proteolipid protein (PLP) and its alternatively spliced isoform DM20 comprise ∼50% of central nervous system (CNS) myelin protein. The two proteins are identical in sequence except for the presence of a 35 amino sequence within the intracellular loop of PLP that is absent in DM20. In this work, we compared the expression of PLP/DM20 in transfected cells, oligodendrocytes and brain. In all 3 tissues, PLP exists as both a monomer and a disulfide-linked dimer; in contrast, DM20 is found mainly as a monomer. PLP dimers were increased by both chemical crosslinking and incubation with hydrogen peroxide, and were mediated by a cysteine at amino acid 108, located within the proximal intracellular loop of both PLP and DM20. The PLP-specific sequence thus influences the accessibility of this cysteine to chemical modification, perhaps as a result of altering protein structure. Consistent with these findings, several mutant PLPs known to cause Pelizaeus-Merzbacher disease form predominantly disulfide-linked, high molecular weight aggregates in transfected COS7 cells that are arrested in the ER and are associated with increased expression of CHOP, a part of the cellular response to unfolded proteins. In contrast, the same mutations in DM20 accumulate fewer high molecular weight disulfide-linked species that are expressed at the cell surface, and are not associated with increased CHOP. Taken together, these data suggest that mutant PLP multimerization, mediated in part by way of cysteine 108, may be part of the pathogenesis of Pelizaeus-Merzbacher disease.

Oligodendroglia - metabolism

Transcription Factor CHOP - genetics

Cross-Linking Reagents - pharmacology

Humans

Cercopithecus aethiops

Molecular Sequence Data

Brain - metabolism

Cystine - chemistry

Transfection

Protein Isoforms - chemistry

Cell Membrane - metabolism

Transcription Factor CHOP - biosynthesis

Myelin Proteolipid Protein - chemistry

Dimerization

Protein Structure, Tertiary

Amino Acid Sequence

Mutagenesis, Site-Directed

Pelizaeus-Merzbacher Disease - genetics

Rats

Cysteine - chemistry

Recombinant Fusion Proteins - chemistry

Unfolded Protein Response

Animals

Myelin Proteolipid Protein - genetics

Protein Conformation

Cells, Cultured - metabolism

COS Cells

Protein Isoforms - genetics

Details

Title: Subtitle: Proteolipid protein dimerization at cysteine 108: Implications for protein structure
Creators: Gurdip Daffu - Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, United States. Gurdip.Daffu@nyumc.org
Jasloveleen Sohi
John Kamholz
Resource Type: Journal article
Publication Details: Neuroscience research, Vol.74(2), pp.144-155
Publisher: Ireland
DOI: 10.1016/j.neures.2012.07.009
PMID: 22902553
ISSN: 0168-0102
eISSN: 1872-8111
Language: English
Date published: 10/2012
Academic Unit: Neurology; Psychiatry
Record Identifier: 9984020762902771

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