Obscurin and KCTD6 regulate cullin-dependent small ankyrin-1 (sAnk1.5) protein turnover.

Protein turnover through cullin-3 is tightly regulated by posttranslational modifications, the COP9-signalosome and BTB/POZ-domain proteins that link cullin-3 to specific substrates for ubiquitylation. Here we report how KCTD6 represents a novel substrate adaptor for cullin-3, effectively regulating protein levels of the muscle ankyrin-1 isoform sAnk1.5.Binding of sAnk1.5 to KCTD6, and ...
its subsequent turnover is regulated through posttranslational modification by nedd8, ubiquitin, and acetylation of C-terminal lysine residues. Presence of sAnk1.5 binding partner obscurin, and mutation of lysine residues increased sAnk1.5 protein levels, as did knockdown of KCTD6 in cardiomyocytes. Obscurin knockout muscle displayed reduced sAnk1.5 levels and mislocalization of the sAnk1.5/KCTD6 complex. Scaffolding functions of obscurin may therefore prevent activation of the cullin-mediated protein degradation machinery and ubiquitylation of sAnk1.5, through sequestration of sAnk1.5/KCTD6 at the sarcomeric M-band, away from the Z-disk associated cullin-3. The interaction of KCTD6 with ankyrin-1 may have implications beyond muscle for hereditary spherocytosis, as KCTD6 is also present in erythrocytes, and erythrocyte ankyrin isoforms contain its mapped minimal binding site.
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Date: May. 09, 2012
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