Journal
BIOORGANIC CHEMISTRY
Volume 116, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2021.105382
Keywords
Bone morphogenetic protein-2; Type-I receptor; Wrist epitope; Peptide cyclization; Hotspot site; Conformational constraint; Chondrocyte senescence
Funding
- National Nature Science Foundation of China [81772426]
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Bone morphogenetic protein-2 (BMP-2) is a key regulator of bone formation and remodeling, as well as implicated in osteoarthritis and chondrocyte senescence. The study identified three discrete hotspot sites as the core region of BMP-2 wrist epitope, which account for a significant portion of the binding potency to BMPR-I. Disulfide-bonded cyclization was found to effectively constrain the peptide conformation and improve binding affinity to BMPR-I.
The bone morphogenetic protein-2 (BMP-2) is an essential regulator of bone formation and remodeling, which has also been implicated in the pathogenesis of osteoarthritis and its closely related chondrocyte senescence. The BMP-2 uses a conformational wrist epitope and a linear knuckle epitope to interact with type-I (BMPR-I) and typeII (BMPR-II) receptors, respectively. Previously, the knuckle epitope has been intensely studied, but the wrist epitope still remains largely unexplored due to its discontinuous nature. In the present work, the intermolecular interaction of BMP-2 with BMPR-I was investigated systematically at structural, energetic and dynamic levels. Three discrete hotspots that represent the key BMPR-I recognition sites of BMP-2 were identified; they are spatially dispersed over the two monomers of BMP-2 dimer and totally account for 83.5 % binding potency of BMP-2 to BMPR-I (hotspot 1: residues 49-70 in monomer 1; hotspot 2: residues 24-31 in monomer 2; hotspot 3: residues 88-107 in monomer 2). Therefore, we defined the three discrete hotspot sites as the core region of wrist epitope; their contribution to the binding increases in the order: hotspot 2 < hotspot 3 < hotspot 1. We demonstrated that the primary hotspot 1 site has a native U-shaped conformation in the full-length BMP-2 protein context, but it cannot maintain in the native conformation when split from the context to obtain a free hotspot-1 peptide, thus largely impairing its binding potency to BMPR-I. We further employed disulfide-bonded cyclization and head-to-tail cyclization to constrain the peptide conformation, and found that only the former can effectively constrain the peptide into native conformation, thus considerably improving its binding affinity to BMPR-I, whereas the latter totally disorders the native conformation, thus rendering the peptide as a full nonbinder of BMPR-I.
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