Deciphering potent MPL activation by the fucose-binding lectin thrombocorticin

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Thrombocorticin (ThC), a marine sponge lectin, activates the thrombopoietin receptor (MPL) via glycan-mediated crosslinking.
• Bacterial lectin PA-IIL is structurally related to ThC but has significantly lower MPL agonist potency.

Purpose of the Study:

• To elucidate the structural basis for differing MPL agonist potencies between ThC and PA-IIL.
• To identify additional structural determinants required for productive MPL receptor activation.

Main Methods:

• Structure-function analyses using ThC and PA-IIL mutants.
• Engineering of lectin oligomeric variants.
• Genome mining for ThC-like bacterial lectins.
• Heterologous expression and MPL agonist activity evaluation.

Main Results:

• MPL activation potency is not solely determined by sugar-binding affinity or apparent oligomeric state.
• Lectins with similar sugar-binding properties exhibited varied agonist activities.
• Engineered oligomeric variants did not consistently correlate with MPL activation potency.
• Three newly identified bacterial lectins showed partial MPL agonist activity.

Conclusions:

• Productive MPL activation necessitates specific structural features beyond sugar-binding capability and oligomeric organization.
• The findings highlight the complexity of lectin-mediated receptor agonism and suggest novel targets for therapeutic development.