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Crystal structure of TDRD3 and methyl-arginine binding characterization of TDRD3, SMN and SPF30
Ke Liu1, Yahong Guo, Haiping Liu
1Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Science, Huazhong Normal University, Wuhan, People's Republic of China.
Abstract:
SMN (Survival motor neuron protein) was characterized as a dimethyl-arginine binding protein over ten years ago. TDRD3 (Tudor domain-containing protein 3) and SPF30 (Splicing factor 30 kDa) were found to bind to various methyl-arginine proteins including Sm proteins as well later on. Recently, TDRD3 was shown to be a transcriptional coactivator, and its transcriptional activity is dependent on its ability to bind arginine-methylated histone marks. In this study, we systematically characterized the binding specificity and affinity of the Tudor domains of these three proteins quantitatively. Our results show that TDRD3 preferentially recognizes asymmetrical dimethylated arginine mark, and SMN is a very promiscuous effector molecule, which recognizes different arginine containing sequence motifs and preferentially binds symmetrical dimethylated arginine. SPF30 is the weakest methyl-arginine binder, which only binds the GAR motif sequences in our library. In addition, we also reported high-resolution crystal structures of the Tudor domain of TDRD3 in complex with two small molecules, which occupy the aromatic cage of TDRD3.
Insights
Survival motor neuron protein (SMN) and Tudor domain-containing protein 3 (TDRD3) bind arginine-methylated proteins with distinct specificities. TDRD3 favors asymmetrical dimethylation, while SMN is promiscuous, binding symmetrical dimethylation.
Area of Science:
- Molecular Biology
- Protein Biochemistry
- Epigenetics
Background:
- Survival motor neuron protein (SMN) is known to bind dimethyl-arginine proteins.
- Tudor domain-containing protein 3 (TDRD3) and Splicing factor 30 kDa (SPF30) also bind methyl-arginine proteins.
- TDRD3 functions as a transcriptional coactivator, dependent on binding arginine-methylated histone marks.
Purpose of the Study:
- To quantitatively characterize the binding specificity and affinity of the Tudor domains of SMN, TDRD3, and SPF30.
- To elucidate the molecular interactions governing methyl-arginine recognition by these proteins.
Main Methods:
- Quantitative binding assays to determine affinity and specificity.
- Systematic characterization of protein-ligand interactions.
- High-resolution crystal structure determination of TDRD3 Tudor domain.
Main Results:
- TDRD3 preferentially recognizes asymmetrical dimethylated arginine marks.
- SMN exhibits promiscuous binding, recognizing various arginine motifs and preferring symmetrical dimethylated arginine.
- SPF30 shows the weakest binding, specifically recognizing GAR motif sequences.
- Crystal structures reveal small molecules binding within the TDRD3 Tudor domain's aromatic cage.
Conclusions:
- SMN, TDRD3, and SPF30 display distinct methyl-arginine binding specificities.
- TDRD3's transcriptional coactivation role is linked to its specific recognition of arginine-methylated histone marks.
- Structural insights into TDRD3 provide a basis for understanding its interactions and potential modulation.
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