Title : Specificity and structure of a high affinity
activin receptor-like kinase 1 (
ALK1 ) signaling complex
Abstract :
- Activin receptor-like kinase 1 ( ALK1 ), an endothelial cell-specific type I receptor of the TGF-β superfamily, is an important regulator of normal blood vessel development as well as pathological tumor angiogenesis
- As such, ALK1 is an important therapeutic target
- Thus, several ALK1-directed agents are currently in clinical trials as anti-angiogenic cancer therapeutics
- Given the biological and clinical importance of the ALK1 signaling pathway, we sought to elucidate the biophysical and structural basis underlying ALK1 signaling
- The TGF-β family ligands BMP9 and BMP10 as well as the three type II TGF-β family receptors ActRIIA , ActRIIB , and BMPRII have been implicated in ALK1 signaling
- Here, we provide a kinetic and thermodynamic analysis of BMP9 and BMP10 interactions with ALK1 and type II receptors
- Our data show that BMP9 displays a significant discrimination in type II receptor binding, whereas BMP10 does not
- We also report the crystal structure of a fully assembled ternary complex of BMP9 with the extracellular domains of ALK1 and ActRIIB
- The structure reveals that the high specificity of ALK1 for BMP9 /10 is determined by a novel orientation of ALK1 with respect to BMP9 , which leads to a unique set of receptor-ligand interactions
- In addition, the structure explains how BMP9 discriminates between low and high affinity type II receptors
- Taken together, our findings provide structural and mechanistic insights into ALK1 signaling that could serve as a basis for novel anti-angiogenic therapies