SMYD5 belongs to a special class of protein lysine methyltransferases with an MYND (Myeloid-Nervy-DEAF1) domain inserted into a SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) domain. Despite recent advances in its functional characterization, the lack of the crystal structure has hindered our understanding of the structure-and-function relationships of this most unique member of the SMYD protein family. Here, we demonstrate the reliability of using AlphaFold structures for understanding the structure and function of SMYD5 by comparing the AlphaFold structures to the known crystal structures of SMYD proteins, using an inter-residue distance maps-based metric. We found that the AlphaFold confidence scores are inversely associated with the refined B-factors and can serve as a structural indicator of conformational flexibility. We also found that the N-terminal sequence of SMYD5, predicted to be a mitochondrial targeting signal, contains a novel non-classical nuclear localization signal. This sequence is structurally flexible and does not have a well-defined conformation, which might facilitate its recognition for SMYD5′s cytonuclear transport. The structure of SMYD5 is unique in many aspects. The “crab”-like structure with a large negatively charged cleft provides a potential binding site for basic molecules such as protamines. The less positively charged MYND domain is associated with the undetectable DNA-binding ability. The most surprising feature is an incomplete target lysine access channel that lacks the evolutionarily conserved tri-aromatic arrangement, being associated with the low H3/H4 catalytic activity. This study expands our understanding of the SMYD protein family from a classical two-lobed structure to a structure of its own kind, being as a fundamental determinant of its functional divergence.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal neoplasms worldwide and represents the vast majority of pancreatic cancer cases. Understanding the molecular pathogenesis and the underlying mechanisms involved in the initiation, maintenance, and progression of PDAC is an urgent need, which may lead to the development of novel therapeutic strategies against this deadly cancer. Here, we review the role of SET and MYND domain-containing protein 2 (SMYD2) in initiating and maintaining PDAC development through methylating multiple tumor suppressors and oncogenic proteins. Given the broad substrate specificity of SMYD2 and its involvement in diverse oncogenic signaling pathways in many other cancers, the mechanistic extrapolation of SMYD2 from these cancers to PDAC may allow for developing new hypotheses about the mechanisms driving PDAC tumor growth and metastasis, supporting a proposition that targeting SMYD2 could be a powerful strategy for the prevention and treatment of PDAC.
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