Are transient protein-protein interactions more dispensable?

Area of Science:

• Molecular Biology
• Biophysics
• Genomics

Background:

• Protein-protein interactions (PPIs) are fundamental to cellular processes and evolution.
• The relative importance and dispensability of transient versus permanent PPIs remain largely unexplored.
• Understanding selective pressures on PPIs is crucial for deciphering cellular function.

Purpose of the Study:

• To compare the proportion of dispensable content in transient and permanent human PPIs.
• To investigate the impact of mutations on the stability of different types of PPIs.
• To estimate the selective constraints acting on transient and permanent PPIs.

Main Methods:

• Construction of a human structural interactome using 3D structural models of PPIs.
• Distinguishing transient from permanent PPIs based on structural and biophysical characteristics.
• Mapping common and disease-associated mutations onto the structural interactome.
• Calculating mutation-induced disruption probabilities for PPIs using structure-based methods and Bayes' theorem.

Main Results:

• A small fraction (<~20%) of both transient and permanent PPIs were estimated to be dispensable (effectively neutral upon disruption).
• Both common (neutral) and disease-associated (deleterious) mutations showed similar probabilities of disrupting transient and permanent PPIs.
• Transient and permanent PPIs exhibit comparable levels of functional importance.

Conclusions:

• Transient and permanent protein-protein interactions are under similarly strong selective constraints in the human interactome.
• The dispensability of PPIs is low across both transient and permanent interaction types.
• This finding challenges assumptions about the functional redundancy of transient interactions.