Journal
MOLECULAR CELL
Volume 15, Issue 3, Pages 485-489Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2004.07.011
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Funding
- NCI NIH HHS [CA09370] Funding Source: Medline
- NICHD NIH HHS [HD13527] Funding Source: Medline
- NIGMS NIH HHS [GM62411] Funding Source: Medline
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A new crystal structure of activin in complex with the extracellular domain of its type II receptor (ActRIIb-ECD) shows that the ligand exhibits an unexpected flexibility. The motion in the activin dimer disrupts its type I receptor interface, which may account for the disparity in its affinity for type I versus type II receptors. We have measured the affinities of activin and its antagonist inhibin for ActRIIb-ECD and found that the affinity of the 2-fold symmetric homodimer activin for ActRIIb-ECD depends on the availability of two spatially coupled ActRIIb-ECD molecules, whereas the affinity of the heterodimer inhibin does not. Our results indicate that activin's affinity for its two receptor types is greatly influenced by their membrane-restricted setting. We propose that activin affinity is modulated by the ligand flexibility and that cooperativity is achieved by binding to two ActRII chains that immobilize activin in a type I binding-competent orientation.
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