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Protein Language Model Identifies Disordered, Conserved Motifs Implicated in Phase Separation.

Yumeng Zhang¹, Jared Zheng², Bin Zhang¹

¹Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.

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Summary

Intrinsically disordered regions (IDRs) are crucial for membraneless organelle (MLO) formation. Evolutionary analysis reveals conserved amino acids within IDRs, suggesting they are key functional units selected for stable MLOs.

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Area of Science:

Biochemistry
Molecular Biology
Evolutionary Biology

Background:

Intrinsically disordered regions (IDRs) are vital for the formation of membraneless organelles (MLOs) through phase separation.
Mutations in IDRs can disrupt protein interactions, leading to altered phase behavior and disease.
Understanding evolutionary constraints on IDRs offers insights into sequence-based phase separation.

Purpose of the Study:

To map residue-level mutational tolerance landscapes of IDRs using the ESM2 protein language model.
To investigate evolutionary conservation patterns within IDRs involved in phase separation.
To explore the relationship between conserved motifs in IDRs and MLO formation.

Main Methods:

Utilized the ESM2 protein language model to predict mutational tolerance.
Analyzed residue-level mutational tolerance landscapes of IDRs.
Performed direct analyses of multiple sequence alignments to confirm conservation.

Main Results:

IDRs actively involved in phase separation exhibit significant amino acid conservation.
Conserved residues include both "stickers" and "spacers" that form continuous sequence motifs.
ESM2 predictions of mutational constraints align with observed conservation in multiple sequence alignments.

Conclusions:

Conserved motifs within IDRs act as functional units under evolutionary selection for stable MLO formation.
Evolutionary analysis, powered by protein language models, reveals the molecular grammar of phase separation.
These findings highlight the importance of evolutionary constraints in understanding the function of disordered protein regions.