Natural mutations of the anti-Mullerian hormone type II receptor found in persistent Mullerian duct syndrome affect ligand binding, signal transduction and cellular transport.
The anti-Müllerian hormone type II (AMHRII) receptor is the primary receptor for anti-Müllerian hormone (AMH), a protein produced by Sertoli cells and responsible for the regression of the Müllerian duct in males. AMHRII is a membrane protein containing an N-terminal extracellular domain (ECD) that binds AMH, a transmembrane domain, and an intracellular domain with serine/threonine kinase activity. Mutations in the AMHRII gene lead to persistent Müllerian duct syndrome in human males. In this paper, we have investigated the effects of 10 AMHRII mutations, namely 4 mutations in the ECD and 6 in the intracellular domain. Molecular models of the extra- and intracellular domains are presented and provide insight into how the structure and function of eight of the mutant receptors, which are still expressed at the cell surface, are affected by their mutations. Interestingly, two soluble receptors truncated upstream of the transmembrane domain are not secreted, unless the transforming growth factor beta type II receptor signal sequence is substituted for the endogenous one. This shows that the AMHRII signal sequence is defective and suggests that AMHRII uses its transmembrane domain instead of its signal sequence to translocate to the endoplasmic reticulum, a characteristic of type III membrane proteins.
Belville
Corinne
C
INSERM U782, 32 rue des Carnets, Clamart F-92140, France.
Maréchal
Jean-Didier
JD
Pennetier
Sophie
S
Carmillo
Paul
P
Masgrau
Laura
L
Messika-Zeitoun
Liza
L
Galey
Julie
J
Machado
Gabrielle
G
Treton
Dominique
D
Gonzalès
Jacques
J
Picard
Jean-Yves
JY
Josso
Nathalie
N
Cate
Richard L
RL
di Clemente
Nathalie
N
D000595:Amino Acid Sequence; D000818:Animals; D054304:Anti-Mullerian Hormone / Q000378:metabolism*; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D012734:Disorders of Sex Development / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D018000:Receptors, Peptide / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction
D008024:Ligands; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; C084621:anti-Mullerian hormone receptor; D054304:Anti-Mullerian Hormone