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Year: 2010  |  Volume: 20  |  Issue: 3  |  Page No.: 348 - 355

Human XTP3-B binds to {alpha}1-antitrypsin variant nullHong Kong via the C-terminal MRH domain in a glycan-dependent manner

D Yamaguchi, D Hu, N Matsumoto and K. Yamamoto    


XTP3-B is a soluble endoplasmic reticulum (ER)-resident protein containing two mannose-6-phosphate receptor homology (MRH) domains in its sequence. XTP3-B interacts with a membrane-associated ubiquitin ligase complex, and, therefore, is thought to participate in ER-associated degradation (ERAD). In this study, the recombinant human XTP3-B fused with IgG-Fc (XTP3-B-Fc), XTP3-B without an N-terminal MRH domain fused with IgG-Fc (XTP3-B1-Fc), or XTP3-B without a C-terminal MRH domain fused with IgG-Fc (XTP3-B2-Fc) were prepared. XTP3-B-Fc and XTP3-B1-Fc bound to Lec1 cells but not to CHO, Lec2, or Lec8 cells, while XTP3-B2-Fc did not bind to any of these cells. The binding of XTP3-B-Fc and XTP3-B1-Fc to Lec1 cells was abrogated by treatment of the cells with endo-β-N-acetylglucosaminidase H, Man1,6Man or Man1,6(Man1,3)Man1,6(Man1,3)Man, or by substitution of Arg428 or Tyr457 in the C-terminal MRH domain with alanine. Arg428 and Tyr457 are homologous to amino acids that mediate glycan binding by the cation-dependent mannose-6-phosphate receptor. An immunoprecipitation experiment using lysates of cells co-expressing wild-type 1-antitrypsin (AT), 1-antitrypsin variant nullHong Kong (ATNHK), and FLAG-tagged XTP3-B, or its mutants, demonstrated that ATNHK, but not AT, specifically co-precipitated with XTP3-B and XTP3-B1. The glycan-binding-deficient XTP3-B2 did not bind either AT or ATNHK. These results suggest that XTP3-B specifically binds to ATNHK, which is a well-known substrate of ERAD, via a C-terminal MRH domain in a glycan-dependent manner.

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