The X-linked intellectual disability gene product and E3 ubiquitin ligase KLHL15 degrades doublecortin proteins to constrain neuronal dendritogenesis.

ABSTRACT: Proper brain development and function requires finely controlled mechanisms for protein turnover, and disruption of genes involved in proteostasis is a common cause of neurodevelopmental disorders. Kelch-like 15 (KLHL15) is a substrate adaptor for cullin3-containing E3 ubiquitin ligases, and KLHL15 gene mutations were recently described as a cause of severe X-linked intellectual disability. Here, we used a bioinformatics approach to identify a family of neuronal microtubule-associated proteins as KLHL15 substrates, which are themselves critical for early brain development. We biochemically validated doublecortin (DCX), also an X-linked disease protein, and doublecortin-like kinase 1 and 2 as bona fide KLHL15 interactors and mapped KLHL15 interaction regions to their tandem DCX domains. Sha

SUBMITTER: Song J 

PROVIDER: S-EPMC7948412 | biostudies-literature | 2021 Jan-Jun

REPOSITORIES: biostudies-literature