Biology:Anti-Müllerian hormone receptor

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Short description: Receptor for anti-Müllerian hormone


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Anti-Müllerian hormone receptor is a receptor for the anti-Müllerian hormone. Furthermore, anti-Mullerian hormone receptor type 2 is a protein in humans that is encoded by the AMHR2 gene.[1]

Function

Both men and women have this gene. AMHR2 is a Type 2 receptor that binds AMH (Anti-mullerian hormone). This hormone is responsible for Mullerian Duct regression in vertebrates once the SRY gene has been expressed. Some animals such as jawless fish do not express either AMH or AMHR2.[2] High circulating AMH continues on after testis development and is secreted from the Sertoli Cells. It has been reported that the loss of function of the AMHR2 gene results in 50% of XY animals to reverse sex to females and also leads to hyperproliferation of mitotically active germ cells, which leads to the sex reversal.[2] AMH binding to the AMHR2 in mammals causes regression of the oviducts, uterus, and upper 2/3 of the vagina. A syndrome called "Persistent Mullerian Duct Syndrome" (PMDS) can occur in human males and results in the uterus, vagina, and uterus being present in virilized male.[3] PMDS can be caused by a genetic mutation of deletions, or missenses, and these males often have undescended testes or cryptorchidism, where one testis fails to descend outside of the body cavity. The majority of these patients will be infertile. In females that are homozygous for the mutation, no abnormalities have been observed. However, heterozygous females have been observed to reach menopause sooner and display a lowered AMH level which also is an indicator of antral follicle count. It is likely that these females reach menopause sooner from having fewer antral follicles, thus more atresia of follicles prior to developing an antrum. These phenotypes were confirmed to be the cause of an AMHR2 mutation from knock out studies performed in mice.

Structure

Annotated 3D structure of AMHR2, based on PDB entry https://doi.org/10.2210/pdb7L0J/pdb

[4]

AMHR2 adopts a typical three-finger toxin fold that is characteristic of the TGF-β type II receptor family to which it belongs. However, it displays a unique extended finger 1 loop (see image) that is critical to effectively binding its ligand, AMH. The palm region and other fingers are also implicated in binding to AMH, but are relatively unremarkable when compared to other TGF-β type II receptors. As such, these interactions do not contribute significantly to the observed ligand specificity for AMH like the finger 1 loop.[4]

Pathology

The anti-Müllerian hormone receptor (Müllerian Inhibiting Substance Type II Receptor) can be responsible for persistent Müllerian duct syndrome.

Müllerian inhibiting substance type II receptor (MISIIR), also known as the Anti-Müllerian Hormone Receptor, is expressed by ovarian, breast, and prostate cancers and these cancer cells have been reported to apoptose in response to exposure to the Müllerian inhibiting substance (MIS).[5]

Antibodies have been developed that specifically target MISIIR and may be useful as vehicles for drugs and toxins for targeted cancer therapy.[6][7][8]

References

  1. ↑ "Entrez Gene: Anti-Mullerian hormone receptor type 2". https://www.ncbi.nlm.nih.gov/gene/269. 
  2. ↑ 2.0 2.1 "Intersex, Hermaphroditism, and Gonadal Plasticity in Vertebrates: Evolution of the Müllerian Duct and Amh/Amhr2 Signaling". Annual Review of Animal Biosciences 7: 149–172. February 2019. doi:10.1146/annurev-animal-020518-114955. PMID 30303691. 
  3. ↑ "AMH and AMHR2 mutations: A spectrum of reproductive phenotypes across vertebrate species". Developmental Biology 455 (1): 1–9. November 2019. doi:10.1016/j.ydbio.2019.07.006. PMID 31301298. 
  4. ↑ 4.0 4.1 "Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family". Proceedings of the National Academy of Sciences of the United States of America 118 (26): e2104809118. June 2021. doi:10.1073/pnas.2104809118. PMID 34155118. Bibcode: 2021PNAS..11804809H. 
  5. ↑ "Human ovarian cancer, cell lines, and primary ascites cells express the human Mullerian inhibiting substance (MIS) type II receptor, bind, and are responsive to MIS". Clinical Cancer Research 5 (11): 3488–3499. November 1999. PMID 10589763. 
  6. ↑ "Isolation of anti-MISIIR scFv molecules from a phage display library by cell sorter biopanning". Cancer Immunology, Immunotherapy 57 (3): 367–378. March 2008. doi:10.1007/s00262-007-0376-2. PMID 17676323. 
  7. ↑ "Development of engineered antibodies specific for the Müllerian inhibiting substance type II receptor: a promising candidate for targeted therapy of ovarian cancer". Molecular Cancer Therapeutics 5 (8): 2096–2105. August 2006. doi:10.1158/1535-7163.MCT-06-0115. PMID 16928831. 
  8. ↑ "The anti-Müllerian hormone type II receptor: insights into the binding domains recognized by a monoclonal antibody and the natural ligand". The Biochemical Journal 379 (Pt 3): 785–793. May 2004. doi:10.1042/BJ20031961. PMID 14750901. 


Further reading

External links



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