Cathepsin A–Neuraminidase 1 protein–protein interface (CTSA–NEU1 interface)

The Cathepsin A (CTSA)–Neuraminidase 1 (NEU1) protein–protein interface is a critical structural and functional junction within the lysosomal multienzyme complex (LMC). CTSA, a serine carboxypeptidase also known as protective protein for beta-galactosidase (PPCA), acts as an essential molecular chaperone for NEU1, ensuring its correct folding, lysosomal trafficking, and protection against intralysosomal proteolysis (UniProt P10619, Q99519). The stability and catalytic activity of NEU1 are strictly dependent on its association with CTSA; dissociation or genetic mutations at this interface lead to rapid NEU1 degradation, a primary cause of the lysosomal storage disorder galactosialidosis (Pshezhetsky & Ashmarina, 2001). Beyond metabolic roles, the CTSA–NEU1 complex translocates to the cell surface, where NEU1 regulates the sialylation status of key signaling receptors such as EGFR, TLR4, and PD-1, thereby influencing oncogenic signaling and immune evasion (Haxho et al., 2016). Consequently, the CTSA–NEU1 interface has emerged as a novel therapeutic target, with research focusing on small molecules or peptides that can disrupt this interaction to downregulate NEU1 activity in cancer or stabilize it in deficiency states. Targeting this interface offers a more specific approach than global enzyme inhibition, potentially minimizing off-target effects on other lysosomal hydrolases.

Other names

PPCA–NEU1 interfaceProtective protein for beta-galactosidase–Sialidase 1 complexLysosomal multienzyme complex interfaceCTSA-NEU1 interaction site

Disruption of the protein-protein interaction to induce NEU1 degradation or stabilization of the complex to restore enzymatic activity.