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Updated: Jun 23, 2025
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Mutations found in cancer patients compromise DNA binding of the winged helix protein STK19
Jian Li1, Xinli Ma1, Xiaoyu Wang1,2
1China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450003, Henan, China.
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.
Insights
Human STK19 is a winged helix protein that binds double-stranded DNA and RNA. Cancer-associated mutations in STK19 compromise its DNA binding, potentially affecting its function in DNA repair and cancer development.
Area of Science:
- Structural biology
- Molecular biology
- Cancer research
Background:
- Serine/threonine protein kinase 19 (STK19) is implicated in melanomagenesis via NRAS activation.
- The kinase activity of STK19 is debated, and it's also linked to transcription-coupled nucleotide excision repair (TC-NER).
Purpose of the Study:
- To determine the crystal structure of human STK19.
- To investigate the DNA/RNA binding properties of STK19.
- To analyze the functional impact of cancer-associated mutations in STK19.
Main Methods:
- X-ray crystallography at 1.32 Å resolution.
- DNA/RNA binding assays.
- Analysis of cancer patient mutations and predicted effects on nuclear localization.
Main Results:
- Human STK19 is a winged helix (WH) protein with three tandem WH domains.
- STK19 exhibits stronger binding to double-stranded DNA/RNA (dsDNA/dsRNA) than single-stranded DNA (ssDNA).
- A positively charged patch on helix WH3-H1 is crucial for dsDNA binding, an unusual feature for WH domains.
- Cancer-associated mutations (K186N, R200W, R215W) in this basic patch impair STK19 DNA binding.
- Mutations disrupting the nuclear localization signal (NLS) may indirectly affect DNA binding by altering nuclear import.
Conclusions:
- STK19 functions as a DNA/RNA-binding protein, not necessarily a kinase.
- The structural and mutational data provide insights into STK19's role in DNA binding and its potential involvement in TC-NER.
- Cancer-associated mutations highlight the importance of STK19's DNA binding and nuclear localization in disease pathogenesis.
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