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

Blanz J, Groth J, Zachos C, Wehling C, Saftig P, Schwake M (2010)
Human Molecular Genetics 19(4): 563-572.

Zeitschriftenaufsatz | Veröffentlicht | Englisch
 
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Autor*in
Blanz, Judith; Groth, Johann; Zachos, Christina; Wehling, Christina; Saftig, Paul; Schwake, MichaelUniBi
Abstract / Bemerkung
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.
Erscheinungsjahr
2010
Zeitschriftentitel
Human Molecular Genetics
Band
19
Ausgabe
4
Seite(n)
563-572
ISSN
0964-6906
eISSN
1460-2083
Page URI
https://pub.uni-bielefeld.de/record/2953347

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Blanz J, Groth J, Zachos C, Wehling C, Saftig P, Schwake M. Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand β-glucocerebrosidase. Human Molecular Genetics. 2010;19(4):563-572.
Blanz, J., Groth, J., Zachos, C., Wehling, C., Saftig, P., & Schwake, M. (2010). Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand β-glucocerebrosidase. Human Molecular Genetics, 19(4), 563-572. https://doi.org/10.1093/hmg/ddp523
Blanz, J., Groth, J., Zachos, C., Wehling, C., Saftig, P., and Schwake, M. (2010). Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand β-glucocerebrosidase. Human Molecular Genetics 19, 563-572.
Blanz, J., et al., 2010. Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand β-glucocerebrosidase. Human Molecular Genetics, 19(4), p 563-572.
J. Blanz, et al., “Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand β-glucocerebrosidase”, Human Molecular Genetics, vol. 19, 2010, pp. 563-572.
Blanz, J., Groth, J., Zachos, C., Wehling, C., Saftig, P., Schwake, M.: Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand β-glucocerebrosidase. Human Molecular Genetics. 19, 563-572 (2010).
Blanz, Judith, Groth, Johann, Zachos, Christina, Wehling, Christina, Saftig, Paul, and Schwake, Michael. “Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand β-glucocerebrosidase”. Human Molecular Genetics 19.4 (2010): 563-572.

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