Bone morphogenetic proteins (BMPs) are an important family of growth factors playing a role in a large number of physiological and pathological processes, including bone homeostasis, tissue regeneration, and cancers. In vivo, BMPs bind successively to both BMP receptors (BMPRs) of type I and type II, and a promiscuity has been reported. In this study, we used biolayer interferometry to perform parallel real-time biosensing and to deduce the kinetic parameters (k_a, k_d) and the equilibrium constant (K_D) for a large range of BMP/BMPR combinations in similar experimental conditions. We selected four members of the BMP family (BMP-2, 4, 7, 9) known for their physiological relevance and studied their interactions with five type-I BMP receptors (ALK1, 2, 3, 5, 6) and three type-II BMP receptors (BMPR-II, ACTR-IIA, ACTR-IIB). We reveal that BMP-2 and BMP-4 behave differently, especially regarding their kinetic interactions and affinities with the type-II BMPR. We found that BMP-7 has a higher affinity for the type-II BMPR receptor ACTR-IIA and a tenfold lower affinity with the type-I receptors. While BMP-9 has a high and similar affinity for all type-II receptors, it can interact with ALK5 and ALK2, in addition to ALK1. Interestingly, we also found that all BMPs can interact with ALK5. The interaction between BMPs and both type-I and type-II receptors in a ternary complex did not reveal further cooperativity. Our work provides a synthetic view of the interactions of these BMPs with their receptors and paves the way for future studies on their cell-type and receptor specific signaling pathways.

中文翻译：

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使用生物层干涉法高通量测量骨形态发生蛋白/骨形态发生蛋白受体相互作用

骨形态发生蛋白 (BMP) 是一个重要的生长因子家族，在许多生理和病理过程中发挥作用，包括骨稳态、组织再生和癌症。在体内，BMP 依次与 I 型和 II 型 BMP 受体 (BMPR) 结合，并且已经报道了混杂。在这项研究中，我们使用生物层干涉测量法进行并行实时生物传感，并推导出动力学参数 (k _a , k _d ) 和平衡常数 (K _D) 用于在类似实验条件下的大范围 BMP/BMPR 组合。我们选择了 BMP 家族的四个成员（BMP-2、4、7、9），以其生理相关性而闻名，并研究了它们与五种 I 型 BMP 受体（ALK1、2、3、5、6）和三种类型- II BMP 受体（BMPR-II、ACTR-IIA、ACTR-IIB）。我们发现 BMP-2 和 BMP-4 表现不同，尤其是在它们与 II 型 BMPR 的动力学相互作用和亲和力方面。我们发现 BMP-7 对 II 型 BMPR 受体 ACTR-IIA 具有更高的亲和力，而与 I 型受体的亲和力低十倍。虽然 BMP-9 对所有 II 型受体具有高且相似的亲和力，但它可以与 ALK5 和 ALK2 以及 ALK1 相互作用。有趣的是，我们还发现所有 BMP 都可以与 ALK5 相互作用。BMP 与三元复合物中 I 型和 II 型受体之间的相互作用没有显示出进一步的协同性。我们的工作提供了这些 BMP 与其受体相互作用的综合观点，并为未来研究它们的细胞类型和受体特异性信号通路铺平了道路。