Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand β-glucocerebrosidase

Judith Blanz, Johann Groth, Christina Zachos, Christina Wehling, Paul Saftig, Michael Schwake*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


Action myoclonus-renal failure syndrome (AMRF) is caused by mutations in the lysosomal integral membrane protein type 2 (LIMP-2/SCARB2). LIMP-2 was identified as a sorting receptor for β-glucocerebrosidase (β-GC), which is defective in Gaucher disease. To date, six AMRF-causing mutations have been described, including splice site, missense and nonsense mutations. All mutations investigated in this study lead to a retention of LIMP-2 in the endoplasmic reticulum (ER) but affect the binding to β-GC differentially. From the three nonsense mutations, only the Q288X mutation was still able to bind to β-GC as efficiently as compared with wild-type LIMP-2, whereas the W146SfsX16 and W178X mutations lost their β-GC-binding capacity almost completely. The LIMP-2 segment 145-288, comprising the nonsense mutations, contains a highly conserved coiled-coil domain, which we suggest determines β-GC binding. In fact, disruption of the helical arrangement and amphiphatic nature of the coiled-coil domain abolishes β-GC binding, and a synthetic peptide comprising the coiled-coil domain of LIMP-2 displays pH-selective multimerization properties. In contrast to the reduced binding properties of the nonsense mutations, the only missense mutation (H363N) found in AMRF leads to increased binding of β-GC to LIMP-2, indicating that this highly conserved histidine modifies the affinity of LIMP-2 to its ligand. With the present study, we demonstrate that disruption of the coiled-coil structure or AMRF disease-causing mutations abolish β-GC binding, indicating the importance of an intact coiled-coil structure for the interaction of LIMP-2 and β-GC.

Original languageEnglish (US)
Article numberddp523
Pages (from-to)563-572
Number of pages10
JournalHuman molecular genetics
Issue number4
StatePublished - Nov 20 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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