kelchlike

Kelch-like, often written kelchlike, denotes a family of proteins characterized by the Kelch repeat motif. In many organisms, Kelch-like proteins are encoded by gene families such as KLHL (Kelch-like) and typically feature an N-terminal BTB/POZ domain in addition to C-terminal Kelch repeats. The name reflects sequence and structural similarity to the Drosophila Kelch protein.

Structure and motifs are central to their function. The Kelch repeats usually assemble into a six-bladed beta-propeller that provides a platform for protein–protein interactions. The BTB/POZ domain mediates dimerization and recruitment of other components, commonly linking to Cullin-3 (CUL3) to form a Cullin-RING ubiquitin ligase (CRL3) complex. A BACK domain is present in many KLHL proteins and contributes to complex stability and substrate engagement. Together, these features enable specific substrate recognition and ubiquitination.

Functionally, many Kelch-like proteins act as substrate adaptors for CRL3 complexes, guiding the ubiquitination and proteasomal degradation of select client proteins. This regulates various cellular processes, including cytoskeletal organization, signaling pathways, and protein turnover. Some Kelch-like proteins may also participate in roles beyond CRL3, such as scaffolding or trafficking.

Distribution and evolution are broad. Kelch-like proteins are found across eukaryotes, with vertebrates showing an expanded set that diversifies substrate specificities for tissue- and context-specific ubiquitination programs.

Clinical significance is noted in human disease. Mutations in certain KLHL genes have been linked to disease, with KLHL3 mutations causing familial hyperkalemic hypertension through disrupted degradation of WNK kinases. Ongoing research continues to clarify the involvement of other Kelch-like proteins in development and disease.

See also: Kelch repeats, BTB/POZ domain, Cullin-RING ubiquitin ligases (CRL3).

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