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Identification and Classification of Position-specific GABAA Receptor Subunit Missense Variants for Their Role In Hippocampal Pyramidal Neurons

Identification and Classification of Position-specific GABA_A Receptor Subunit Missense Variants for Their Role In Hippocampal Pyramidal Neurons

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Structural basis for potency differences between GDF8 and GDF11.

Ryan G Walker¹, Magdalena Czepnik¹, Erich J Goebel¹

¹Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH, 45267, USA.

|March 5, 2017

Summary

This summary is machine-generated.

Growth/differentiation factor 11 (GDF11) is a more potent activator of SMAD2/3 signaling than GDF8, despite their structural similarity. Unique structural features of GDF11 enhance its signaling potency compared to GDF8.

Keywords:

Ligands Myostatin Receptor Structure Transforming growth factor β (TGFβ)

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Area of Science:

Molecular Biology
Biochemistry
Cell Signaling

Background:

Growth/differentiation factor 8 (GDF8) and GDF11 are highly similar members of the transforming growth factor β (TGFβ) family.
GDF8 negatively regulates muscle growth, while GDF11's function in age-related dysfunction is debated.
This study investigates whether GDF8 and GDF11 are functionally identical.

Purpose of the Study:

To compare the signaling and structural properties of GDF8 and GDF11.
To determine if GDF8 and GDF11 are functionally distinct.
To elucidate the structural basis for any functional differences.

Main Methods:

Comparative analysis of GDF8 and GDF11 signaling.
Resolution of crystal structures for GDF11:FS288 complex, apo-GDF8, and apo-GDF11.
Site-directed mutagenesis by substituting GDF11 residues into GDF8.

Main Results:

GDF11 is a more potent activator of SMAD2/3 signaling than GDF8.
GDF11 signals more effectively through ALK4/5/7 receptors compared to GDF8.
Crystal structures revealed unique properties at the type I receptor binding site for both ligands.
Substitution of GDF11 residues into GDF8 enhanced GDF8 activity.

Conclusions:

Distinct structural features in GDF11 enhance its signaling potency relative to GDF8.
These findings highlight functional differences between GDF8 and GDF11.
The precise biological consequences of these structural and signaling differences require further investigation.