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Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase
Shuang Yang1, Xiangdong Zheng2, Chao Lu3
1MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China;
Genes & Development
|July 31, 2016
Summary
Histone mutations drive cancers by inhibiting SETD2. Crystal structures reveal how mutated H3K36 peptides bind and inhibit SETD2, offering insights into cancer mechanisms.
Area of Science:
- Molecular biology
- Structural biology
- Oncology
Background:
- Point mutations in histone genes are emerging cancer drivers.
- H3K36M/I mutations are oncogenic, inhibiting histone methyltransferases like SETD2.
Purpose of the Study:
- To elucidate the structural basis of SETD2 inhibition by oncohistone mutations.
- To understand the molecular mechanisms of H3K36M/I interaction with SETD2.
Main Methods:
- X-ray crystallography to determine the structure of SETD2 catalytic domain bound to H3K36M/I peptides.
- Biochemical assays to validate the functional impact of the observed interactions.
Main Results:
- Crystal structures of SETD2 catalytic domain complexed with H3K36M or H3K36I peptides and SAH were obtained.
- The SETD2 catalytic domain adopts an open conformation upon binding.
- Mutated peptides bind within a newly identified substrate channel, explaining SETD2 inhibition.
Conclusions:
- Structural and biochemical data reveal the molecular basis for oncohistone recognition and SETD2 inhibition.
- These findings provide a foundation for understanding the role of H3K36M/I mutations in tumorigenesis.
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