Update on the Kelch-like (KLHL) gene family

Abstract

The Kelch-like (KLHL) gene family encodes a group of proteins that generally possess a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. BTB domains facilitate protein binding and dimerization. The BACK domain has no known function yet is of functional importance since mutations in this domain are associated with disease. Kelch domains form a tertiary structure of β-propellers that have a role in extracellular functions, morphology, and binding to other proteins. Presently, 42 KLHL genes have been classified by the HUGO Gene Nomenclature Committee (HGNC), and they are found across multiple human chromosomes. The KLHL family is conserved throughout evolution. Phylogenetic analysis of KLHL family members suggests that it can be subdivided into three subgroups with KLHL11 as the oldest member and KLHL9 as the youngest. Several KLHL proteins bind to the E3 ligase cullin 3 and are known to be involved in ubiquitination. KLHL genes are responsible for several Mendelian diseases and have been associated with cancer. Further investigation of this family of proteins will likely provide valuable insights into basic biology and human disease.

Figure 1

Schematic diagram of KLHL family members drawn to scale with amino acid numbers listed on the right. ‘BTB,’ ‘BACK,’ and ‘K’ indicate the BTB domain, BACK domain, and Kelch domains, respectively. In case of multiple isoforms, only the first one is depicted. Data was collected from [20] using a motif scan with Pfam HMMs (global or local models).

Figure 2

Phylogenetic tree of KLHL proteins with evolutionary distances shown next to each protein. Amino acid sequences were obtained from [21], and the alignment was created with ClustalO from [22]. The Cladogram was created using ClustalW2-Phylogeny from [23].