The LIMP-2/SCARB2 binding motif on acid {beta}-glucosidase: basic and applied implications for Gaucher disease and associated neurodegenerative diseases [Metabolism]

September 8th, 2014 by Liou, B., Haffey, W. D., Greis, K. D., Grabowski, G. A.

The acid β-glucosidase (GCase, glucocerbro-sidase) binding sequence to lysosomal integral membrane protein 2 (LIMP-2), the receptor for intracellular GCase trafficking to the lysosome has been identified. Heterologous expression of deletion constructs, the available GCase crystal structures, and binding and colocalization of identified peptides or mutant GCases were used to identify and characterize a highly conserved 11 amino acid sequence, DSPIIVDITKD, within human GCase. The binding to LIMP-2 is not dependent upon a single amino acid, but GCase interactions with LIMP-2 are heavily influenced by D399 and the di-isoleucines, I402 and I403. Single alanine substitutions at any of these decreases GCase binding to LIMP-2 and alters its pH dependent binding as well as diminishing GCase trafficking to the lysosome and increasing significantly GCase secretion. Enterovirus 71 also binds to LIMP-2 (a.k.a. SCARB2) on the external surface of the plasma membrane. However, the LIMP-2/SCARB2 binding sequences for Enterovirus 71 and GCase are not similar indicating that LIMP-2/SCARB2 may have multiple or overlapping binding sites with differing specificities. These findings have therapeutic implications for the production of GCase and the distribution of this enzyme that is delivered to various organs.
  • Posted in Journal of Biological Chemistry, Publications
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