PRG2

Eosinophil major basic protein 1 (MBP-1), a highly cationic protein (~13.8 kDa, pI ~11.4) that is the predominant constituent of the crystalline core in eosinophil secondary granules. Synthesized as a 222-amino acid precursor with an acidic, heavily glycosylated prosegment (~9 kDa) that neutralizes the toxicity of the basic mature domain during biosynthesis. The prosegment contains N-linked, O-linked, and glycosaminoglycan chains (hence "proteoglycan 2"), raising precursor mass to 30-50 kDa. Upon maturation, the prosegment is proteolytically cleaved in the Golgi/secretory granule, yielding the active 117-residue MBP that is stored in paracrystalline arrays within granules. Structurally, MBP adopts a C-type lectin-like fold but lacks Ca2+-binding sites; instead presents a highly cationic surface for binding sulfated polysaccharides like heparin and heparan sulfate. Primary function: cytotoxic effector in antiparasitic defense - directly damages helminth larvae membranes and cuticles (experimental knockout mice show impaired killing of Strongyloides and filarial worms). Also exhibits broad antimicrobial activity against bacteria and fungi via membrane disruption. Immunomodulatory roles: triggers degranulation of mast cells and basophils (histamine release), activates neutrophils (superoxide production) and platelets. Toxic to host cells - causes epithelial damage and denudation in allergic diseases. In asthma, acts as allosteric antagonist of M2 muscarinic acetylcholine receptors on parasympathetic neurons, disabling inhibitory feedback and causing bronchospasm and airway hyperresponsiveness. Inhibits heparanase (first known endogenous heparanase inhibitor). In chronic settings, induces TGF-β and MMP-1 expression, promoting fibrosis and tissue remodeling. Dual biology: the proMBP form is abundantly expressed in placenta during pregnancy and secreted into maternal circulation, where it forms disulfide-linked 1:1 complexes with PAPP-A (pregnancy-associated plasma protein A), inhibiting this metalloprotease's cleavage of IGFBPs and thereby modulating IGF signaling for fetal growth. ProMBP also binds angiotensinogen and complement C3dg. The PAPP-A/proMBP complex is a clinical biomarker in first-trimester Down syndrome screening. ProMBP is non-toxic (acidic prosegment renders it inert), contrasting with the highly cytotoxic mature MBP released from eosinophils. MBP levels correlate with disease severity in asthma, eosinophilic esophagitis, and other eosinophil-driven conditions.