The pathogenicity, structural and functional exploration of human HMGB1 single nucleotide polymorphisms using in...

Area of Science:

• Genetics and Molecular Biology
• Immunology
• Cancer Research

Background:

• Human High Mobility Group Box 1 (HMGB1) is a multifunctional protein involved in immune regulation and cellular functions.
• Mutations in HMGB1 can lead to immune-related diseases and cancer.
• The impact of non-synonymous HMGB1 mutations on its structure-function relationship remains largely unexplored.

Purpose of the Study:

• To investigate the implications of single nucleotide polymorphisms (SNPs) on the structure and function of human HMGB1.
• To identify specific mutations that are deleterious and disease-causing.
• To elucidate the molecular mechanisms by which these mutations affect HMGB1 activity.

Main Methods:

• Sequence-based homology methods
• Supervised learning methods
• Structure-based computational analyses
• Analysis of mutations in relation to functional domains (e.g., B-box, TLR binding region)

Main Results:

• Identified 58 non-synonymous mutations in human HMGB1.
• Classified R10T (rs61742222) and F103C (rs61733675) as the most deleterious SNPs.
• R10T mutation alters the B-box domain structure and predicted to affect DNA binding and protein interactions.
• F103C mutation occurs in the TLR and cytokine binding region, potentially affecting signaling pathways.
• Both identified mutations hinder HMGB1's DNA binding and TLR/cytokine binding activities.

Conclusions:

• R10T and F103C are potent disease-causing mutations in human HMGB1.
• These mutations disrupt critical HMGB1 functions, including DNA binding and interactions with TLRs and cytokines.
• Findings provide molecular insights into HMGB1's role in cancer and immunological diseases.