Hepatitis C virus RNA replication in human stellate cells regulates gene expression of extracellular matrix-related molecules |
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Authors: | Watanabe Noriyuki Aizaki Hideki Matsuura Tomokazu Kojima Soichi Wakita Takaji Suzuki Tetsuro |
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Affiliation: | Department of Pharmacology, SUNY Upstate Medical University, 750 E. Adams St., Syracuse, NY 13210, USA |
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Abstract: | Erlin1 and erlin2 are highly homologous, ∼40 kDa, endoplasmic reticulum membrane proteins that assemble into a ring-shaped complex with a mass of ∼2 MDa. How this complex is formed is not understood, but appears to involve multiple interactions, including a coiled-coil region that mediates lower-order erlin assembly, and a short hydrophobic region, termed the “assembly domain”, that mediates higher-order assembly into ∼2 MDa complexes. Here we have used molecular modeling, mutagenesis and cross-linking to examine the role of the assembly domain in higher-order assembly. We find (i) that the assembly domains of erlin1 and erlin2 are amphipathic helices, (ii) that erlin1 alone and erlin2 alone can assemble into ∼2 MDa complexes, (iii) that higher-order assembly is strongly inhibited by point mutations to the assembly domain, (iv) that three interacting hydrophobic residues in the assembly domain and aromaticity are essential for higher-order assembly, and (iv) that while erlins1 and 2 are equally capable of forming lower-order homo- and hetero-oligomers, hetero-oligomers are the most prevalent form when erlin1 and erlin2 are co-expressed. Overall, we conclude that the ∼2 MDa erlin1/2 complex is composed of an assemblage of lower-order hetero-oligomers, probably heterotrimers, linked together by assembly domain hydrophobic residues. |
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Keywords: | Abbreviations: E1, erlin1 E2, erlin2 ER, endoplasmic reticulum HA, hemagglutinin DSS, disuccinimidyl suberate |
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