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Mollusk hemocyanins, among the largest known proteins, are used as immunostimulants in biomedical and clinical applications. The hemocyanin of the Chilean gastropod Concholepas concholepas (CCH) exhibits unique properties, which makes it safe and effective for human immunotherapy, as observed in animal models of bladder cancer and melanoma, and dendritical cell vaccine trials. Despite its potential, the structure and amino acid sequence of CCH remain unknown. This study reports two sequence fragments of CCH, representing three complete functional units (FUs). We also determined the high-resolution (1.5 Å) X-ray crystal structure of an “FU-g type” from the CCHB subunit. This structure enables in-depth analysis of chemical interactions at the copper-binding center and unveils an unusual, truncated N-glycosylation pattern. These features are linked to eliciting more robust immunological responses in animals, offering insights into CCH’s enhanced immunostimulatory properties and opening new avenues for its potential applications in biomedical research and therapies.
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•High-resolution FU structure unveils an unusual N-glycosylation pattern•Sequence information for Concholepas concholepas hemocyanin (CCH)•Two leucine at the Cu2O2 cluster explain the absence of phenol oxidase activity
Muñoz et al. determined the high-resolution structure of a functional unit (FU) from the immunogenic hemocyanin from Concholepas concholepas and report three FU sequences. Structural analysis reveals an unusual, truncated N-glycosylation and two leucines that hinder access to the Cu2O2 cluster, explaining the absence of phenol oxidase activity in hemocyanin.