Kelchdomain

Kelchdomain is a protein domain characterized by the Kelch motif, a short sequence unit that repeats to form a beta-propeller structure. Each repeat is typically about 50 amino acids long, and multiple repeats assemble into a multi-bladed propeller, most commonly with six blades though the exact number can vary. The Kelch domain can occur on its own or as part of larger proteins that include other interaction modules.

Function and architecture: The Kelch domain primarily mediates protein–protein interactions and substrate recognition. In many Kelch-like proteins, the Kelch domain acts as the substrate-binding module of ubiquitin ligase complexes, particularly CUL3-based E3 ligases, guiding specific targets for ubiquitination and degradation. An archetypal example is KEAP1, whose Kelch domain binds the transcription factor Nrf2 and regulates its stability in response to cellular redox status.

Distribution and evolution: The Kelch domain is widespread in eukaryotes and has diversified through gene duplication and domain shuffling, contributing to large KLHL (Kelch-like) protein families in animals and plants. The structural conservation of the beta-propeller fold supports versatile substrate recognition across different contexts while allowing lineage-specific expansions.

Research and applications: Kelch-domain proteins are studied for roles in development, signaling, and disease, including cancer and neurodegeneration. Because the interface between the Kelch domain and its substrates can be a druggable target, research explores small molecules and peptides that modulate these interactions to influence proteostasis and signaling pathways.

See also: Kelch repeats, beta-propeller, CUL3 E3 ubiquitin ligases, KEAP1.