Combined in vitro and in silico analyses of missense mutations in GNPTAB provide new insights into the molecular bases of mucolipidosis II and III alpha/beta.
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| Abstract |
Mucolipidosis (ML) II and III alpha/beta are inherited lysosomal storage disorders caused by mutations in GNPTAB encoding the α/β-precursor of GlcNAc-1-phosphotransferase. This enzyme catalyzes the initial step in the modification of more than 70 lysosomal enzymes with mannose 6-phosphate residues to ensure their intracellular targeting to lysosomes. The so-called stealth domains in the α- and β-subunit of GlcNAc-1-phosphotransferase were thought to be involved in substrate recognition and/or catalysis. Here, we performed in silico alignment analysis of stealth domain-containing phosphotransferases and showed that the amino acid residues Glu389 , Asp408 , His956 , and Arg986 are highly conserved between different phosphotransferases. Interestingly, mutations in these residues were identified in patients with MLII and MLIII alpha/beta. To further support the in silico findings, we also provide experimental data demonstrating that these four amino acid residues are strictly required for GlcNAc-1-phosphotransferase activity and thus may be directly involved in the enzymatic catalysis.
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| Authors | Tatyana Danyukova, Nataniel F Ludwig, Renata V Velho, Frederike L Harms, Nilay Güneş, Henning Tidow, Ida V Schwartz, Beyhan Tüysüz, Sandra Pohl |
| Journal | Human mutation (Hum Mutat) Vol. 41 Issue 1 Pg. 133-139 (01 2020) ISSN: 1098-1004 [Electronic] United States |
| PMID | 31579991 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | © 2019 The Authors. Human Mutation published by Wiley Periodicals, Inc. |
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