CoDIAC: A comprehensive approach for interaction analysis provides insights into SH2 domain function and regulation

Area of Science:

• * Molecular and Structural Biology
• * Bioinformatics and Computational Biology

Background:

• * Protein domains are fundamental structural and functional units of proteins.
• * Evolutionary processes lead to diverse domain configurations, enabling new interaction specificities.
• * Understanding domain-domain interfaces is crucial for deciphering protein function and regulation.

Purpose of the Study:

• * To develop a structure-based computational approach for mapping protein domain interfaces.
• * To investigate the conservation and selectivity of domain-domain interactions.
• * To identify conserved posttranslational modifications (PTMs) at interaction interfaces and their effects on protein function.

Main Methods:

• * Development of an open-source Python package, Comprehensive Domain Interface Analysis of Contacts (CoDIAC).
• * Structure-based interface analysis to map macromolecular and intraprotein interfaces.
• * Application of CoDIAC to the human Src homology 2 (SH2) domain family.

Main Results:

• * CoDIAC successfully mapped domain interfaces, providing insights into domain selectivity and conservation.
• * Analysis of SH2 domains revealed coordinated regulation of binding interfaces by tyrosine and serine/threonine phosphorylation and acetylation.
• * Identified potential PTMs influencing SH2 domain interaction specificity and protein signaling.

Conclusions:

• * CoDIAC is a versatile tool for analyzing protein domain interfaces and molecular interactions.
• * Coordinated regulation by multiple PTMs suggests complex signaling networks governing protein activity.
• * The study provides a framework for understanding how PTMs modulate protein interactions and function.