RRC ID 4307
著者 Tsuda H, Han SM, Yang Y, Tong C, Lin YQ, Mohan K, Haueter C, Zoghbi A, Harati Y, Kwan J, Miller MA, Bellen HJ.
タイトル The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors.
ジャーナル Cell
Abstract VAP proteins (human VAPB/ALS8, Drosophila VAP33, and C. elegans VPR-1) are homologous proteins with an amino-terminal major sperm protein (MSP) domain and a transmembrane domain. The MSP domain is named for its similarity to the C. elegans MSP protein, a sperm-derived hormone that binds to the Eph receptor and induces oocyte maturation. A point mutation (P56S) in the MSP domain of human VAPB is associated with Amyotrophic lateral sclerosis (ALS), but the mechanisms underlying the pathogenesis are poorly understood. Here we show that the MSP domains of VAP proteins are cleaved and secreted ligands for Eph receptors. The P58S mutation in VAP33 leads to a failure to secrete the MSP domain as well as ubiquitination, accumulation of inclusions in the endoplasmic reticulum, and an unfolded protein response. We propose that VAP MSP domains are secreted and act as diffusible hormones for Eph receptors. This work provides insight into mechanisms that may impact the pathogenesis of ALS.
巻・号 133(6)
ページ 963-77
公開日 2008-6-13
DOI 10.1016/j.cell.2008.04.039
PII S0092-8674(08)00613-2
PMID 18555774
PMC PMC2494862
MeSH Amyotrophic Lateral Sclerosis / metabolism Animals Animals, Genetically Modified Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / chemistry Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cell Line Drosophila Proteins / chemistry Drosophila Proteins / genetics Drosophila Proteins / metabolism* Drosophila melanogaster / metabolism Endoplasmic Reticulum / metabolism Humans Ligands Membrane Proteins / chemistry Membrane Proteins / genetics Membrane Proteins / metabolism* Protein Folding Protein Structure, Tertiary Receptors, Eph Family / metabolism* Ubiquitination Vesicular Transport Proteins / chemistry Vesicular Transport Proteins / genetics Vesicular Transport Proteins / metabolism*
IF 38.637
引用数 145
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
リソース情報
線虫 tm1411