KLHL12: Human kelch-like 12
PDB Code: 2VPJ
Kelch-like 12 is a member of the BTB/kelch (Broad-Complex, Tramtrack and Bric a brac) repeat family. The protein consists of a BTB domain, a BACK domain (BTB and C-terminal Kelch), and a C-terminal Kelch domain comprising six Kelch repeats.
KLHL12 is ubiquitously expressed in the cytoplasm with high levels in lung, pancreas, prostate, spleen, and testis. It has been shown to associate with the wnt-signaling component Dishevelled (Dsh) forming an E3 ubiquitin ligase complex that promotes Dsh poly-ubiquitination and degradation in a Wnt-dependent manner. Thus, the interaction of KLHL12 with Dsh antagonizes the Wnt–β-catenin pathway adding an additional level of regulation by protein degradation in addition to the well studied control mechanism of β-catenin degradation by the Cullin-1 based SCFβ-TrCP complex.
KLHL12 has been identified as one of the autoantigens in Sjögren's syndrome, which is a is a chronic autoimmune disease with prominent sicca complaints caused by lymphocytic infiltration and destruction of salivary and lachrymal glands, giving rise to deficient function and leading to dry eyes and dry mouth. Expression of KHLH12 in salivary glands suggests a potential role of KHLH12 in this disease. Here we report the structure of the KHLH12 Kelch domain at 1.85 Å resolution.
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