Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 23, Issue 13, Pages 2490-2504Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E12-01-0052
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Funding
- Muscular Dystrophy Association [MDA68929]
- NIH [K99/R00, 1K99HL107744-01, P30-NS047101, P30-CA23100]
- University of California, San Diego (UCSD)
- Cardiovascular Fellowship
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR059334]
- National Heart, Lung, and Blood Institute
- Medical Research Council
- BHF
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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. In this paper, we report how potassium channel tetramerization domain containing 6 (KCTD6) represents a novel substrate adaptor for cullin-3, effectively regulating protein levels of the muscle small ankyrin-1 isoform 5 (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. The presence of the 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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