Abstract
BackgroundMembers of the TGF-β superfamily are characterized by a highly promiscuous ligand-receptor interaction as is readily apparent from the numeral discrepancy of only seven type I and five type II receptors available for more than 40 ligands. Structural and functional studies have been used to address the question of how specific signals can be deduced from a limited number of receptor combinations and to unravel the molecular mechanisms underlying the protein-protein recognition that allow such limited specificity.Principal FindingsIn this study we have investigated how an antigen binding antibody fragment (Fab) raised against the extracellular domain of the BMP receptor type IA (BMPR-IA) recognizes the receptor's BMP-2 binding epitope and thereby neutralizes BMP-2 receptor activation. The crystal structure of the complex of the BMPR-IA ectodomain bound to the Fab AbD1556 revealed that the contact surface of BMPR-IA overlaps extensively with the contact surface for BMP-2 interaction. Although the structural epitopes of BMPR-IA to both binding partners coincides, the structures of BMPR-IA in the two complexes differ significantly. In contrast to the structural differences, alanine-scanning mutagenesis of BMPR-IA showed that the functional determinants for binding to the antibody and BMP-2 are almost identical.ConclusionsComparing the structures of BMPR-IA bound to BMP-2 or bound to the Fab AbD1556 with the structure of unbound BMPR-IA shows that binding of BMPR-IA to its interaction partners follows a selection fit mechanism, possibly indicating that the ligand promiscuity of BMPR-IA is inherently encoded by structural adaptability. The functional and structural analysis of the BMPR-IA binding antibody AbD1556 mimicking the BMP-2 binding epitope may thus pave the way for the design of low-molecular weight synthetic receptor binders/inhibitors.
Highlights
Bone morphogenetic proteins (BMPs) are secreted multifunctional signaling proteins that belong to the TGF-b (Transforming Growth Factor b) superfamily [1]
Comparing the structures of BMP receptor type IA (BMPR-IA) bound to BMP-2 or bound to the Fab AbD1556 with the structure of unbound BMPR-IA shows that binding of BMPR-IA to its interaction partners follows a selection fit mechanism, possibly indicating that the ligand promiscuity of BMPR-IA is inherently encoded by structural adaptability
The functional and structural analysis of the BMPR-IA binding antibody AbD1556 mimicking the BMP-2 binding epitope may pave the way for the design of low-molecular weight synthetic receptor binders/inhibitors
Summary
Bone morphogenetic proteins (BMPs) are secreted multifunctional signaling proteins that belong to the TGF-b (Transforming Growth Factor b) superfamily [1]. Members of the BMP subfamily play important roles during development, maintenance and regeneration of tissues and organs in almost all vertebrates and non-vertebrate animals [2,3]. Their malfunction during the signalling process can lead to multiple diseases including skeletal malformations, cardiovascular and metabolic diseases, muscular disorders and cancer [4]. Signal transduction of TGF-b proteins is initiated by binding to two types of receptors named type I and type II [1,5] Both receptor classes share a cysteine-rich extracellular domain, a single transmembrane segment and a cytoplasmic serine/ threonine-kinase domain.
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