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Review
. 2022 Jun 22:13:927824.
doi: 10.3389/fendo.2022.927824. eCollection 2022.

Molecular Mechanisms of AMH Signaling

James A Howard  1 , Kaitlin N Hart  1 , Thomas B Thompson  2
Affiliations
Review

Molecular Mechanisms of AMH Signaling

James A Howard et al. Front Endocrinol (Lausanne). .

Abstract

Anti-Müllerian Hormone (AMH) is a secreted glycoprotein hormone with critical roles in reproductive development and regulation. Its chemical and mechanistic similarities to members of the Transforming Growth Factor β (TGF-β) family have led to its placement within this signaling family. As a member of the TGF-β family, AMH exists as a noncovalent complex of a large N-terminal prodomain and smaller C-terminal mature signaling domain. To produce a signal, the mature domain will bind to the extracellular domains of two type I and two type II receptors which results in an intracellular SMAD signal. Interestingly, as will be discussed in this review, AMH possesses several unique characteristics which set it apart from other ligands within the TGF-β family. In particular, AMH has a dedicated type II receptor, Anti-Müllerian Hormone Receptor Type II (AMHR2), making this interaction intriguing mechanistically as well as therapeutically. Further, the prodomain of AMH has remained largely uncharacterized, despite being the largest prodomain within the family. Recent advancements in the field have provided valuable insight into the molecular mechanisms of AMH signaling, however there are still many areas of AMH signaling not understood. Herein, we will discuss what is known about the biochemistry of AMH and AMHR2, focusing on recent advances in understanding the unique characteristics of AMH signaling and the molecular mechanisms of receptor engagement.

Keywords: activin; anti-müllerian hormone (AMH); anti-müllerian hormone receptor type II (AMHR2); bone morphogenetic protein (BMP); cell signaling; persistent müllerian duct syndrome (PMDS); prodomain; transforming growth factor-β (TGF-β).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
A schematic of AMH and AMHR2 processing and receptor assembly. (A) The full translated sequences of AMH and AMHR2 undergo processing to cleave the signal sequence. In AMH, PCs will cleave at the solid bar, separating the prodomain and mature domain, while alternative processing may occur at the dashed bar. In AMHR2, dashed bars represent alternative splicing sites. (B) Assembled AMH pro-complex, which may or may not be cleaved. (C) AMH-driven receptor assembly at the cell surface, resulting from AMH binding AMHR2 and prodomain dissociation. Type I receptors are activated and in turn activate BMP R-Smads.
Figure 2
Figure 2
Structural features of AMH and AMHR2. Diagram of the structure of mature AMH (A) and AMHR2 ECD (B). (C) Comparison of the binding modes of each ligand class to a type II receptor. (D) Mapping of PMDS mutations (83), indicated by red spheres, to the binary complex. (E) Sequence of AMH and AMHR2 annotated with secondary structure features and highlighted in red with the above PMDS mutations.
See this image and copyright information in PMC

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