Structure of Smad1 MH1/DNA complex reveals distinctive rearrangements of BMP and TGF-β effectors

Nithya BabuRajendran, Paaventhan Palasingam, Kamesh Narasimhan, Wenjie Sun, Shyam Prabhakar, Ralf Jauch, Prasanna Kolatkar

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Smad1 is a downstream effector of the BMP signaling pathway that binds regulatory DNA to execute gene expression programs leading to, for example, the maintenance of pluripotency in mice. On the contrary, the TGF-β-activated Smad3 triggers strikingly different programs such as mesodermal differentiation in early development. Because Smad1 and Smad3 contain identical amino acids at the DNA contact interface it is unclear how they elicit distinctive bioactivities. Here, we report the crystal structure of the MH1 domain of Smad1 bound to a palindromic Smad binding element. Surprisingly, the DNA contact interface of Smad1 is drastically rearranged when compared to Smad3. The N-terminal helix 1 of Smad1 is dislodged from its intramolecular binding site and adopts a domain swapped arrangement with a symmetry-related molecule. As a consequence, helix 2 kinks away from the double helix disabling several key phosphate backbone interactions. Thermal melting analysis corroborates a decompacted conformation of Smad1 and DNA binding assays indicate a lower overall affinity of Smad1 to DNA but increased cooperativity when binding to palindromic DNA motifs. These findings suggest that Smad1 and Smad3 evolved differential qualities to assemble on composite DNA elements and to engage in co-factor interactions by remodeling their N-termini.

Original languageEnglish
Article numbergkq046
Pages (from-to)3477-3488
Number of pages12
JournalNucleic Acids Research
Volume38
Issue number10
DOIs
Publication statusPublished - 10 Feb 2010
Externally publishedYes

Fingerprint

DNA
Nucleic Acid Conformation
Nucleotide Motifs
Freezing
Hot Temperature
Phosphates
Binding Sites
Maintenance
Gene Expression
Amino Acids

ASJC Scopus subject areas

  • Genetics

Cite this

BabuRajendran, N., Palasingam, P., Narasimhan, K., Sun, W., Prabhakar, S., Jauch, R., & Kolatkar, P. (2010). Structure of Smad1 MH1/DNA complex reveals distinctive rearrangements of BMP and TGF-β effectors. Nucleic Acids Research, 38(10), 3477-3488. [gkq046]. https://doi.org/10.1093/nar/gkq046

Structure of Smad1 MH1/DNA complex reveals distinctive rearrangements of BMP and TGF-β effectors. / BabuRajendran, Nithya; Palasingam, Paaventhan; Narasimhan, Kamesh; Sun, Wenjie; Prabhakar, Shyam; Jauch, Ralf; Kolatkar, Prasanna.

In: Nucleic Acids Research, Vol. 38, No. 10, gkq046, 10.02.2010, p. 3477-3488.

Research output: Contribution to journalArticle

BabuRajendran, N, Palasingam, P, Narasimhan, K, Sun, W, Prabhakar, S, Jauch, R & Kolatkar, P 2010, 'Structure of Smad1 MH1/DNA complex reveals distinctive rearrangements of BMP and TGF-β effectors', Nucleic Acids Research, vol. 38, no. 10, gkq046, pp. 3477-3488. https://doi.org/10.1093/nar/gkq046
BabuRajendran N, Palasingam P, Narasimhan K, Sun W, Prabhakar S, Jauch R et al. Structure of Smad1 MH1/DNA complex reveals distinctive rearrangements of BMP and TGF-β effectors. Nucleic Acids Research. 2010 Feb 10;38(10):3477-3488. gkq046. https://doi.org/10.1093/nar/gkq046
BabuRajendran, Nithya ; Palasingam, Paaventhan ; Narasimhan, Kamesh ; Sun, Wenjie ; Prabhakar, Shyam ; Jauch, Ralf ; Kolatkar, Prasanna. / Structure of Smad1 MH1/DNA complex reveals distinctive rearrangements of BMP and TGF-β effectors. In: Nucleic Acids Research. 2010 ; Vol. 38, No. 10. pp. 3477-3488.
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