Mutations found in cancer patients compromise DNA binding of the winged helix protein STK19

Abstract Serine/threonine protein kinase 19 (STK19) has been reported to phosphorylate and activate oncogenic NRAS to promote melanomagenesis. However, concerns have been raised about whether STK19 is a kinase. STK19 has also been identified as a putative factor involved in the transcription-coupled nucleotide excision repair (TC-NER) pathway. In this study, we determined the 1.32 Å crystal structure of human STK19. The structure reveals that STK19 is a winged helix (WH) protein consisting of three tandem WH domains. STK19 binds more strongly to double-stranded DNA and RNA (dsDNA/dsRNA) than to ssDNA. A positively charged patch centered on helix WH3-H1 contributes to dsDNA binding, which is unusual because the WH domain typically uses helix H3 as the recognition helix. Importantly, mutations of the conserved residues in the basic patch, K186N, R200W, and R215W, are found in cancer patients, and these mutations compromise STK19 DNA binding. Other mutations have been predicted to produce a similar effect, including two mutations that disrupt the nuclear localization signal (NLS) motif. These mutations may indirectly impact the DNA binding capacity of STK19 by interfering with its nuclear localization.