Mapping the Functional Epitopes of Human Growth Hormone: Integrating Structural and Evolutionary Data with Clinical Variants
Publisher DOI
PubMed ID
41614776
Abstract
Human growth hormone (GH) exerts its pleiotropic effects by binding to its receptor (GHR), leading to receptor dimerization and activation. We combined structural, evolutionary, and genetic analyses to elucidate the critical determinants of GH-GHR interaction and the impact of disease-causing mutations. Protein contact analysis revealed the specific amino acid residues involved in two distinct binding interfaces between GH and two chains of GHR. ConSurf analysis demonstrated significant sequence conservation in the receptor-binding regions of GH across species, highlighting their functional importance. A comprehensive list of known disease-causing mutations in GH was compiled and mapped to these binding interfaces and conserved regions. Computational site-directed mutagenesis (SDM) analysis predicted the impact of several mutations on protein stability, revealing both stabilizing and destabilizing effects. Sequence comparisons with orthologs from various species further supported the evolutionary conservation of key functional residues. Integrated analysis of contact residues between GH and GHR showed a strong correlation between receptor-binding residues, evolutionary conservation, and the occurrence of disease-associated mutations. These findings underscore the critical role of specific GH residues in mediating high-affinity interactions with its receptor and how mutations in these conserved contact points can disrupt binding affinity and/or protein stability, ultimately leading to growth disorders. This multi-faceted approach provides valuable insights into the molecular mechanisms underlying growth hormone deficiency and related syndromes.
Date Issued
2025-12-03
Publication Type
Article
Subjects
GH1
•
IGHD
•
growth disorders
•
growth hormone
•
human genome variation
•
population genetics
•
structural analysis
Language(s)
en
Author(s)
Journal
Current Issues in Molecular Biology
Publisher
MDPI
ISSN
1467-3045
1467-3037
Access(Rights)
Unknown