Title : Structure of
myostatin ·
follistatin-like 3: N-terminal
domains of
follistatin-type molecules exhibit alternate modes of binding
Abstract :
- TGF-β family ligands are involved in a variety of critical physiological processes
- For instance, the TGF-β ligand myostatin is a staunch negative regulator of muscle growth and a therapeutic target for muscle-wasting disorders
- Therefore, it is important to understand the molecular mechanisms of TGF-β family regulation
- One form of regulation is through inhibition by extracellular antagonists such as the follistatin ( Fst )-type proteins
- Myostatin is tightly controlled by Fst-like 3 ( Fstl3 ), which is the only Fst-type molecule that has been identified in the serum bound to myostatin
- Here, we present the crystal structure of myostatin in complex with Fstl3
- The structure reveals that the N-terminal domain (ND) of Fstl3 interacts uniquely with myostatin as compared with activin A , because it utilizes different surfaces on the ligand
- This results in conformational differences in the ND of Fstl3 that alter its position in the type I receptor-binding site of the ligand
- We also show that single point mutations in the ND of Fstl3 are detrimental to ligand binding, whereas corresponding mutations in Fst have little effect
- Overall, we have shown that the NDs of Fst-type molecules exhibit distinctive modes of ligand binding, which may affect overall affinity of ligand· Fst-type protein complexes