Structure of the immunoregulatory sialidase NEU1.

Alexei Gorelik, Katalin Illes, Mohammad T Mazhab-Jafari, Bhushan Nagar

Science advances 2023 May 19

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Sialic acids linked to glycoproteins and glycolipids are important mediators of cell and protein recognition events. These sugar residues are removed by neuraminidases (sialidases). Neuraminidase-1 (sialidase-1 or NEU1) is a ubiquitously expressed mammalian sialidase located in lysosomes and on the cell membrane. Because of its modulation of multiple signaling processes, it is a potential therapeutic target for cancers and immune disorders. Genetic defects in NEU1 or in its protective protein cathepsin A (PPCA, CTSA) cause the lysosomal storage diseases sialidosis and galactosialidosis. To further our understanding of this enzyme's function at the molecular level, we determined the three-dimensional structure of murine NEU1. The enzyme oligomerizes through two self-association interfaces and displays a wide substrate-binding cavity. A catalytic loop adopts an inactive conformation. We propose a mechanism of activation involving a conformational change in this loop upon binding to its protective protein. These findings may facilitate the development of selective inhibitor and agonist therapies.

Citation

Alexei Gorelik, Katalin Illes, Mohammad T Mazhab-Jafari, Bhushan Nagar. Structure of the immunoregulatory sialidase NEU1. Science advances. 2023 May 19;9(20):eadf8169