A Host–Guest Relationship in Bone Morphogenetic Protein Receptor-II Defines Specificity in Ligand–Receptor Recognition

Abstract

One of the most intriguing questions confronting the Bone Morphogenetic Protein family is the mechanism of ligand recognition, since there are more ligands than receptors. Crystal structures of two type II receptors ActR-II and BMPR-II are essentially identical, and a loop structure (A-loop) has been suggested to play a role in determining ligand specificity. Solution biophysical study showed mutations of several A-loop residues in these two receptors exert different ligand binding effects. Thus, the issues of mechanism of ligand recognition and specificity remain unresolved. We examined effects of mutations of residues Y40, G47, and S107 in BMPR-II receptor. These residues are not identified in contact with the ligand in the BMP-7-BMPR-II complex, but are found mutated in genetic diseases. They are likely to be useful in identifying their roles in differentiating the various BMP ligands. Spectroscopic probing revealed little mutation-induced structural change in BMPR-II. Ligand binding studies revealed that Y40 plays a significant role in differentiating three distinct ligands; G47 and S107 affect ligand binding to a lesser extent. The role of the A-loop in ActR-II or BMPR-II is dependent on the host sequence of the receptor extracellular domain (ECD) in which it is embedded, suggesting a host-guest relationship between the A-loop and the rest of the ECD. Computational analysis demonstrated a long-range connectivity between Y40, G47, and S107 and other locations in BMPR-II. An integration of these results on functional energetics and protein structures clearly demonstrate, for the first time, an intra-domain communication network within BMPR-II.

N-linked glycosylation of the bone morphogenetic protein receptor type 2 (BMPR2) enhances ligand binding

“…1C–D). Moreover, the proximity of N110 in BMPR2 to the ligand binding hydrophobic patch [27] suggests that N-glycosylation of BMPR2 could be functionally significant.…”

“…This plasticity has largely been attributed to differences at the amino acid level affecting three-dimensional structure [20–27] or post-translational modifications (PTM) that occur on specific ligands [28]. However, considerably less attention has been paid to the role that PTMs in the receptor extra-cellular domain (ECD) might play in altering receptor:ligand interactions in the BMP pathway.…”

Abnormal Trafficking of Endogenously Expressed BMPR2 Mutant Allelic Products in Patients with Heritable Pulmonary Arterial Hypertension

“…These findings suggest that the Bmpr2ΔEx2 is retained in the ER as a result of mis-folding of the mutant product. Since deletion of Exon2 in Bmpr2ΔEx2 results in a loss of 3/10 cysteine residues located in the ligand-binding domain of Bmpr2, it is likely that mis-folding occurs as a result of a breakdown in paired cysteine disulfide bond formation which is required for correct Bmpr2 structure and folding in the ER [46-49]. …”

Structural Energy Landscapes and Plasticity of the Microstates of Apo Escherichia coli cAMP Receptor Protein

“…Within this ensemble, the free energy of each conformational state, ΔG c , is calculated with a surface area parametrization that has been validated experimentally. 27,28 By setting an equilibrium constant (K c ) between conformer c and the folded state {K c = exp[−ΔG c /(RT)]}, we define the probability (P c ) of each conformer as…”

“…Residue-Specific Connectivity.-In a graphic presentation of the coupling between residues i and j, we introduce the parameter residue-specific connectivity (RSC). 27 In the context of the Monte Carlo sampling method, we use the correlation function to define the RSC as…”