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 MH2 Domain | |
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Structure:
 The MH2 domain contains a central b-sandwich and a three helix bundle with a single strand on one end and a loop-helix region on the other end. This is structurally similar to the FHA domain, hinting at potential functional similarities for peptide interactions. Interaction between the b-sheet of the Smad2 MH2 domain and a rigid coil on SARA are essential for specificity, while interactions between the MH2 three-helix bundle and the SARA b-strand contribute to binding affinity. The complete interaction results in close packing of the two structures and buries approximately 2500A2 of surface area. The MH2 of R-Smads contains a positively charged groove next to the L3 loop that is believed to interact with a conserved region of the cytoplasmic domain of the type I TGFb receptor. Homo-oligomerization of Smad4 involves the interaction of the loop-helix region of one subunit packing against the three-helix bundle from another subunit. The L3 loop of Smad4 is thought to mediate hetero-oligomerization with phosphorylated R-Smads. The figure shows the MH2 domain of human Smad2.
Structure Reference:
Wu, G. et al. (2000) Science 287(5450): 92-97. PDB: 1DEV.
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Domain binding and function:
Smad proteins are divided into three functional classes: the comediator Smads (co-Smads), the receptor-regulated Smads (R-Smads) and the inhibitory Smads (I-Smads). These Smad proteins are highly conserved within their N-terminal MH1 domain and C-terminal MH2 domain. The MH2 domain contains a central β-sandwich, with a conserved loop-helix region capable of binding phospho-serine residues. Upon receptor engaging ligand, R-Smads are recruited to the pSer-X-pSer motif on the TGFβ receptor-I and the R-Smad is in turn phosphorylated on two Ser residues of the C-terminal SSXS motif. This allows for disassociation from the receptor and heterocomplex formation with the co-Smad through its MH2 domain. In addition, phosphorylated Smad2 forms a symmetric homotrimer, with both the phosphorylated C-terminus and the N-terminal extension from one MH2 domain reaching out to interact with an adjacent domain. Notably, the pSer binding surface on the MH2 domain of Smad2 and Smad4 are frequently mutated in cancers.
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Examples of Proteins:
| MH2 domain protein |
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Binding partner |
| Smad1 (R-Smad) |  |
type1 TGF-b receptor BMPR-I group of receptors ALK1 group of receptors |
| Smad2 (R-Smad) | |
SARA |
| Smad4 (Co-Smad) | |
Smad4 to form trimers by homo-oligomerization |
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Referenced in part on Cell Signaling Technology Website, Reference Section on Protein Domains. We gratefully acknowledge the following contributors:
Piers Nash1, Dan Lin3, Kathleen Binns2, Clark Wells2, Rob Ingham2, Terry Kubiseski2, Bernard Liu1, Matt Smith2,3, Ivan Blasutig2,3, Maria Sierra1, Caesar Lim2,3, Michael Arc1, Jim Fawcett2 and Tony Pawson2,3.
1. Ben May Institute for Cancer Research, The University of Chicago, Chicago, Illinois, 60637, USA
2. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada
3. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
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