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bioRxiv · 10.1101/2024.04.01.587627

Structural Basis of Non-Latent Signaling by the Anti-Mullerian Hormone Procomplex

Howard, J. A.·Hok, L.·Cate, R. L.·Sanford, N. J.·Hart, K. N.·Leach, E. A.·Bruening, A. S.·Pepin, D.·Donahoe, P. K.·Thompson, T. B.
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Abstract

Most TGF{beta} family ligands exist as procomplexes consisting of a prodomain noncovalently bound to a growth factor (GF); Whereas some prodomains confer latency, the Anti-Mullerian Hormone (AMH) prodomain maintains a remarkably high affinity for the GF yet remains active. Using single particle EM methods, we show the AMH prodomain consists of two subdomains: a vestigial TGF{beta} prodomain-like fold and a novel, helical bundle GF-binding domain, the result of an exon insertion 450 million years ago, that engages both receptor epitopes. When associated with the prodomain, the AMH GF is distorted into a strained, open conformation whose closure upon bivalent binding of AMHR2 displaces the prodomain through a conformational shift mechanism to allow for signaling.

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Howard, J. A., Hok, L., Cate, R. L., Sanford, N. J., Hart, K. N., Leach, E. A., Bruening, A. S., Pepin, D., Donahoe, P. K., Thompson, T. B.. 2024-04-01. Structural Basis of Non-Latent Signaling by the Anti-Mullerian Hormone Procomplex. https://doi.org/10.1101/2024.04.01.587627

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