Structural characterization of the α-N-acetylglucosaminidase, a key enzyme in the pathogenesis of Sanfilippo syndrome B.

Gabriel Birrane, Anne-Laure Dassier, Alla Romashko, Dianna Lundberg, Kevin Holmes, Thomas Cottle, Angela W Norton, Bohong Zhang, Michael F Concino, Muthuraman Meiyappan

Journal: Journal of structural biology 2020;205(3):65-71

PMID: 30802506

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Abstract

Mucopolysaccharidosis III B (MPS III-B) is a rare lysosomal storage disorder caused by deficiencies in Alpha-N-acetylglucosaminidase (NAGLU) for which there is currently no cure, and present treatment is largely supportive. Understanding the structure of NAGLU may allow for identification of novel therapeutic targets for MPS III-B. Here we describe the first crystal structure of human NAGLU, determined to a resolution of 2.3 Å. The crystal structure reveals a novel homotrimeric configuration, maintained primarily by hydrophobic and electrostatic interactions via domain II of three contiguous domains from the N- to C-terminus. The active site cleft is located between domains II and III. Catalytic glutamate residues, E316 and E446, are located at the top of the (α/β) barrel structure in domain II. We utilized the three-dimensional structure of NAGLU to map several MPS III-B mutations, and hypothesize their functional consequences. Revealing atomic level structural information about this critical lysosomal enzyme paves the way for the design of novel therapeutics to target the underlying causes of MPS III-B.

Address: Division of Experimental Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, 99 Brookline Ave., Boston, MA 02215, United States.; Discovery Therapeutics, Research-US, Takeda Pharmaceutical Company Limited, 125 Binney St., Cambridge, MA 02142, United States.; Discovery Therapeutics, Research-US, Takeda Pharmaceutical Company Limited, 125 Binney St., Cambridge, MA 02142, United States. Electronic address: [email protected].

DOI: 10.1016/j.jsb.2019.02.005

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MeSH Terms: Acetylglucosamine, Acetylglucosaminidase, Amino Acid Motifs, Catalytic Domain, Cell Line, Tumor, Cloning, Molecular, Crystallography, X-Ray, Fibroblasts, Gene Expression, Genetic Vectors, Humans, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Mucopolysaccharidosis III, Mutation, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Structure, Tertiary, Recombinant Proteins, Static Electricity, Structural Homology, Protein, Substrate Specificity