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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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. / Danyukova, Tatyana; Ludwig, Nataniel F; Velho, Renata Voltolini; Harms, Frederike L; Güneş, Nilay; Tidow, Henning; Schwartz, Ida V; Tüysüz, Beyhan; Pohl, Sandra.
In: HUM MUTAT, Vol. 41, No. 1, 01.2020, p. 133-139.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - 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
AU - Danyukova, Tatyana
AU - Ludwig, Nataniel F
AU - Velho, Renata Voltolini
AU - Harms, Frederike L
AU - Güneş, Nilay
AU - Tidow, Henning
AU - Schwartz, Ida V
AU - Tüysüz, Beyhan
AU - Pohl, Sandra
N1 - © 2019 The Authors. Human Mutation published by Wiley Periodicals, Inc.
PY - 2020/1
Y1 - 2020/1
N2 - 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.
AB - 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.
U2 - 10.1002/humu.23928
DO - 10.1002/humu.23928
M3 - SCORING: Journal article
C2 - 31579991
VL - 41
SP - 133
EP - 139
JO - HUM MUTAT
JF - HUM MUTAT
SN - 1059-7794
IS - 1
ER -
