Mapping the Functional Epitopes of Human Growth Hormone: Integrating Structural and Evolutionary Data with Clinical...

Area of Science:

• Molecular biology
• Genetics
• Evolutionary biology

Background:

• Human growth hormone (GH) mediates its effects by binding to the growth hormone receptor (GHR), initiating signaling cascades.
• Understanding the molecular basis of GH-GHR interaction is vital for diagnosing and treating growth disorders.

Purpose of the Study:

• To identify critical determinants of GH-GHR interaction using structural, evolutionary, and genetic analyses.
• To investigate the impact of disease-causing mutations on GH-GHR binding and protein stability.

Main Methods:

• Protein contact analysis to identify GH-GHR binding interfaces.
• ConSurf analysis to assess evolutionary conservation of GH residues.
• Compilation and mapping of disease-associated GH mutations.
• Computational site-directed mutagenesis (SDM) to predict mutation effects on protein stability.

Main Results:

• Two distinct binding interfaces between GH and GHR were identified.
• Key GH residues involved in receptor binding show significant evolutionary conservation.
• Disease-causing mutations frequently occur at conserved, contact residues.
• Mutations can destabilize GH protein structure and/or impair GHR binding.

Conclusions:

• Specific GH residues are critical for high-affinity GHR binding.
• Mutations in conserved GH contact points disrupt binding and/or stability, leading to growth disorders.
• This study provides molecular insights into growth hormone deficiency and related conditions.