In-Depth Study of Low-Complexity Domains: From Structural Diversity to Disease Mechanisms

TL;DR

Low-complexity domains in proteins are now recognized as important for cellular functions and disease mechanisms, with roles in protein interactions and neurodegenerative disorders.

Contribution

This review systematically explores structural, functional, and pathological aspects of low-complexity domains and highlights recent methodological advances.

Findings

LCDs exhibit intrinsic disorder and conformational dynamics, influencing β-sheet formation and phase separation.

Dysfunction in LCDs is linked to diseases like ALS, AD, and Ewing sarcoma through mechanisms like aggregation and aberrant phase separation.

Advances in methods like cryo-EM, fluorescence microscopy, and AI simulations are enhancing LCD research.

Abstract

Low-complexity domains (LCDs) are protein regions characterized by a simple amino acid composition and low sequence complexity, as they are typically composed of repeats or a limited set of a few amino acids. Historically dismissed as “garbage sequences”, these regions are now acknowledged as critical functional elements. This review systematically explores the structural characteristics, biological functions, pathological roles, and research methodologies associated with LCDs. Structurally, LCDs are marked by intrinsic disorder and conformational dynamics, with their amino acid composition (e.g., G/Y-rich, Q-rich, S/R-rich, P-rich) dictating structural tendencies (e.g., β-sheet formation, phase separation ability). Functionally, LCDs mediate protein–protein interactions, drive liquid–liquid phase separation (LLPS) to form biomolecular condensates, and play roles in signal transduction, transcriptional regulation, cytoskeletal organization, and nuclear pore transportation. Pathologically, LCD dysfunction—such as aberrant phase separation or aggregation—is implicated in neurodegenerative diseases (e.g., ALS, AD), cancer (e.g., Ewing sarcoma), and prion diseases. We also summarize the methodological advances in LCD research, including biochemical (CD, NMR), structural (cryo-EM, HDX-MS), cellular (fluorescence microscopy), and computational (MD simulations, AI prediction) approaches. Finally, we highlight current challenges (e.g., structural heterogeneity, causal ambiguity of phase separation) and future directions (e.g., single-molecule techniques, AI-driven LCD design, targeted therapies). This review provides a comprehensive perspective on LCDs, illuminating their pivotal roles in cellular physiology and disease, and offering insights for future research and therapeutic development.

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