Disruption of structural and functional integrity of α2-macroglobulin by cathepsin E

Mitsue Shibata, Hideaki Sakai, Eiko Sakai, Kuniaki Okamoto, Kazuhisa Nishishita, Yoshiyuki Yasuda, Yuzo Kato, Kenji Yamamoto

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18 Citations (Scopus)

Abstract

α2-Macroglobulin (α2M) is an abundant glycoprotein with the intrinsic capacity for capturing diverse proteins for rapid delivery into cells. After internalization by the receptor-mediated endocytosis, α2M-protein complexes were rapidly degraded in the endolysosome system. Although this is an important pathway for clearance of both α2M and biological targets, little is known about the nature of α2M degradation in the endolysosome system. To investigate the possible involvement of intracellular aspartic proteinases in the disruption of structural and functional integrity of α2M in the endolysosome system, we examined the capacity of α2M for interacting with cathepsin E and cathepsin D under acidic conditions and the nature of its degradation. α2M was efficiently associated with cathepsin E under acidic conditions to form noncovalent complexes and rapidly degraded through the generation of three major proteins with apparent molecular masses of 90, 85 and 30 kDa. Parallel with this reaction, α2M resulted in the rapid loss of its antiproteolytic activity. Analysis of the N-terminal amino-acid sequences of these proteins revealed that α2M was selectively cleaved at the Phe811-Leu812 bond in about 100mer downstream of the bait region. In contrast, little change was observed for α2M treated by cathepsin D under the same conditions. Together, the synthetic SPAFLA peptide corresponding to the Ser808-Ala813 sequence of human α2M, which contains the cathepsin E-cleavage site, was selectively cleaved by cathepsin E, but not cathepsin D. These results suggest the possible involvement of cathepsin E in disruption of the structural and functional integrity of α2M in the endolysosome system.

Original languageEnglish
Pages (from-to)1189-1198
Number of pages10
JournalEuropean Journal of Biochemistry
Volume270
Issue number6
DOIs
Publication statusPublished - Mar 1 2003
Externally publishedYes

Keywords

  • Aspartic proteinase
  • Cathepsin D
  • Cathepsin E
  • Endolysosome system
  • α-macroglobulin

ASJC Scopus subject areas

  • Biochemistry

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    Shibata, M., Sakai, H., Sakai, E., Okamoto, K., Nishishita, K., Yasuda, Y., Kato, Y., & Yamamoto, K. (2003). Disruption of structural and functional integrity of α2-macroglobulin by cathepsin E. European Journal of Biochemistry, 270(6), 1189-1198. https://doi.org/10.1046/j.1432-1033.2003.03479.x