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Amino Acid 72 of Mouse And Human GDF9 Mature Domain Is Responsible For Altered Homodimer Bioactivities But Has Subtle Effects On GDF9:BMP15 Heterodimer Activities.
MedLine Citation:
PMID:  25253739     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are oocyte-secreted paralogs of the transforming growth factor beta (TGFbeta) superfamily. In mammals, these two growth factors play critical roles in folliculogenesis. As previously reported, an arginine in the pre-helix loop of GDF5 defines the high binding specificity to its type 1 receptor. Interestingly, bioactive mouse GDF9 and human BMP15 share the conserved arginine in the pre-helix loop, but their low activity counterparts (mouse BMP15 and human GDF9) have a glycine or a proline instead. To address the question whether the arginine residue defines the different activities of GDF9 and BMP15 homodimers and their heterodimers in human and mouse, we used site-directed mutagenesis to change the species-specific residues in human and mouse proteins, and examined their activities in our in vitro assays. While amino acid 72 of mature GDF9 is responsible for altered homodimer bioactivities, neither the corresponding BMP15 amino acid 62 nor the intact pre-helix loop is indispensable for BMP15 homodimer activity. However, amino acid 72 in GDF9 only has only subtle effects on GDF9:BMP15 heterodimer activity. Based on previous studies and our recent findings, we provide hypothetical models to understand the molecular mechanism to define activities of the homodimeric and heterodimeric ligands. The arginine residue in the pre-helix loop of GDF9 homodimer may prevent the inhibition from its pro-domain or directly alter receptor binding, but this residue in GDF9 does not significantly affect the heterodimer activity due to suggested conformational changes during heterodimer formation.
Authors:
Jia Peng; Karen Wigglesworth; Adithya Rangarajan; John J Eppig; Thomas B Thompson; Martin M Matzuk
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-9-24
Journal Detail:
Title:  Biology of reproduction     Volume:  -     ISSN:  1529-7268     ISO Abbreviation:  Biol. Reprod.     Publication Date:  2014 Sep 
Date Detail:
Created Date:  2014-9-25     Completed Date:  -     Revised Date:  2014-9-26    
Medline Journal Info:
Nlm Unique ID:  0207224     Medline TA:  Biol Reprod     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright 2014 by The Society for the Study of Reproduction.
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