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Author Spotlight: A Computational Approach to Decipher Amino Acid Preferences in Multispecific Protein-Protein Interactions

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Published on: January 26, 2024

Evolutionary Pro-To-Thr Mutation in the Intrinsically Disordered Domain of ANP32 Family Members Modulates Their

Blanca Baños-Jaime¹, Ana B Uceda-Mayo¹, Francisco Rivero-Rodríguez¹

¹Institute for Chemical Research (IIQ), Scientific Research Center "Isla de la Cartuja" (cicCartuja), University of Seville-CSIC, Avda. Americo Vespucio 49, Seville, 41092, Spain.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)

|January 31, 2025

Summary

Gene duplication drives protein evolution, with disordered regions like ANP32A/ANP32B C-terminal LCARs showing sequence differences. These variations impact target binding and cellular roles, influencing disease.

Keywords:

HuR cytochrome c intrinsically disordered domain isothermal calorimetry nuclear magnetic resonance

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Published on: July 30, 2014

Area of Science:

Molecular Biology
Protein Evolution
Genomics

Background:

Gene duplication is a key driver of protein evolution, leading to novel functions.
Paralogous proteins, like ANP32A and ANP32B, often diverge in disordered regions, impacting their roles.
Tissue-specific expression patterns correlate with sequence variations in these proteins.

Purpose of the Study:

To investigate the structural and functional differences between ANP32A and ANP32B, focusing on their C-terminal disordered regions.
To understand how sequence variations in low-complexity-acidic-regions (LCARs) affect protein structure and target interactions.
To elucidate the functional consequences of these differences in relation to cytochrome c and HuR binding.

Main Methods:

Comparative sequence analysis of ANP32A and ANP32B.
Structural analysis of C-terminal low-complexity-acidic-regions (LCARs).
Computational modeling to assess the impact of amino acid substitutions on protein structure and dynamics.
Investigation of protein-protein interactions with cytochrome c and HuR.

Main Results:

Significant sequence differences exist in the C-terminal LCARs of ANP32A and ANP32B, despite similar N-terminal domains.
A Pro-to-Thr substitution near the nuclear localization signal (NLS) in ANP32B influences LCAR compactness compared to ANP32A.
These structural variations lead to divergent binding modes for targets such as cytochrome c and the RNA-binding protein HuR.

Conclusions:

Sequence variations in disordered regions, particularly LCARs, are critical for the functional divergence of paralogous proteins like ANP32A and ANP32B.
Differential regulation of ANP32A and ANP32B impacts the cellular roles of cytochrome c and HuR.
Understanding these differences is crucial for explaining distinct roles in disease pathogenesis.