PDBsum entry: 1khu

Transcription

PDB id: 1khu

Contents

Protein chains

198 a.a. *

184 a.a. *

Waters ×586

* Residue conservation analysis

PDB id:

1khu

Name:

Transcription

Title:

Smad1 crystal structure reveals the details of bmp signaling pathway

Structure:

Smad1. Chain: a, b, c, d. Fragment: dwb

Source:

Homo sapiens. Human. Organism_taxid: 9606

Biol. unit:

Trimer (from PDB file)

Resolution:

2.50Å R-factor: 0.239 R-free: 0.274

Authors:

B.Y.Qin,K.Lin

Key ref:

B.Y.Qin et al. (2001). Structural basis of Smad1 activation by receptor kinase phosphorylation. Mol Cell, 8, 1303-1312. PubMed id: 11779505 DOI: 10.1016/S1097-2765(01)00417-8

Date:

01-Dec-01 Release date: 12-Dec-01

Protein chains

Q15797  (SMAD1_HUMAN) -  Mothers against decapentaplegic homolog 1

Seq: 465 a.a.

Struc: 198 a.a.

Protein chain

Q15797  (SMAD1_HUMAN) -  Mothers against decapentaplegic homolog 1

Seq: 465 a.a.

Struc: 184 a.a.

 Gene Ontology (GO) functional annotation 

• Cellular component: intracellular (1 term)
• Biological process: regulation of transcription, DNA-dependent (1 term)

DOI no: 10.1016/S1097-2765(01)00417-8

Mol Cell 8:1303-1312 (2001)

PubMed id: 11779505

Structural basis of Smad1 activation by receptor kinase phosphorylation.

B.Y.Qin, B.M.Chacko, S.S.Lam, M.P.de Caestecker, J.J.Correia, K.Lin.

ABSTRACT

Phosphorylation of Smad1 at the conserved carboxyl terminal SVS sequence activates BMP signaling. Here we report the crystal structure of the Smad1 MH2 domain in a conformation that reveals the structural effects of phosphorylation and a molecular mechanism for activation. Within a trimeric subunit assembly, the SVS sequence docks near two putative phosphoserine binding pockets of the neighboring molecule, in a position ready to interact upon phosphorylation. The MH2 domain undergoes concerted conformational changes upon activation, which signal Smad1 dissociation from the receptor kinase for subsequent heteromeric assembly with Smad4. Biochemical and modeling studies reveal unique favorable interactions within the Smad1/Smad4 heteromeric interface, providing a structural basis for their association in signaling.

Selected figure(s)

Figure 2.
Figure 2. Structural Basis of Phosphorylation-Induced Smad1 Trimerization(A) Crystal structure of S1LCS showing the subunit packing arrangement in the asymmetric unit. The four subunits in the asymmetric unit are shown by the ribbon representation. The 3-fold NCS axis is perpendicular to the page and indicated by a cross. The 3-fold crystallographic axis is indicated by a horizontal line. The regions where the C-terminal tail interacts with the L3 loop are circled. The L3 loops are colored black.(B) Stereo view of the Fo-Fc omit map of the L3 loop/tail region contoured at 2.5 σ. The residues lining the tail binding pocket are labeled in black, while the tail residues are labeled in red.(C) Surface electrostatic potential presentation of the L3 loop/tail interaction. The residues lining the tail binding pocket are labeled in black, while the tail residues are labeled in red.(D) Stereo view of the L3 loop/tail interaction, where the L3 loop is in the closed conformation. The L3 loop main chain and side chain are colored in cyan and green, respectively. The C-terminal tail is colored in pink. The location of Gly419 is shown by a sphere. H-bond interactions are shown by red dotted line.(E) Stereo view of the unliganded L3 loop in subunit B, where the L3 loop is in the open conformation. The L3 loop main chain and side chain are colored in cyan and green, respectively. The location of Gly419 is shown by a sphere.(F) Smad1 trimerization induces tilting of the three-helix bundle structure. The Smad2-SARA complex structure is superimposed on subunit B of the Smad1 trimer over the β sandwich core (Smad1 residues used are 273–302, 309–359, 371–387, 413–417, and 434–442; Smad2 residues used are 270–299, 307–357, 369–385, 411–415, and 432–440). The β sandwich core was used for superposition because it is conserved in all Smad proteins, and is likely to be structurally rigid. After superposition, the rms deviation of the β sandwich core Cα trace is 0.7 Å. However, the rms deviation of the Cα trace when superimposed over the entire structure (β sandwich core and the three-helix bundle structure) is 1.6 Å, indicating that there is relative movement between the β sandwich core and the three-helix bundle structure. A similar result is obtained when the Smad2-SARA structure is superimposed on subunit A or C, but is not shown for clarity. The Smad2 MH2 domain is colored in red. The SARA SBD is colored in pink. The arrows indicate the direction of helix 4 and 5 movement.

Figure 4.
Figure 4. Basis of Preferential Interaction between Smad4 and R-Smad As Revealed by Structural Modeling of the Smad4-Smad1 Heterotrimeric Complex(A) The three-helix bundle structure of Smad4 is tilted more toward the subunit interface (indicated by a black circle) to promote heterotrimeric assembly between Smad1 and Smad4. The Smad1 subunits are colored in green. The Smad4 subunit is shown in red. The modeling was performed by superimposing the Smad4 subunit on top of the Smad1 subunit C over the β sandwich core (Smad4 residues used for the superimposition are 322–341, 346–356, 360–391, 397–411, 424–441, 499–510, and 517–541; Smad1 residues used are 270–289, 292–302, 307–338, 343–357, 369–386, 410–421, and 428–452). The model was then examined for subunit interactions. The model created this way maintains all key trimeric contacts observed in the Smad1 trimer and contains additional favorable interactions. The black arrows show the direction of the helix movement.(B) Closeup view of the Smad1 homotrimeric interface. The side chains of helix 1 and 4 are colored in green and pink, respectively.(C) Closeup view of the hypothetical model of the Smad1-Smad4 heterotrimeric interface. The side chains of Smad1 helix 1 are colored in green. The side chains of Smad4 helix 4 are colored in pink. Potential H-bonds are shown by red dotted lines.(D) Sequence alignment of helix 1 and 4 in Smad proteins. The residues are color-coded according to (B) and (C). Conserved residues are marked with an asterisk (*).

The above figures are reprinted by permission from Cell Press: Mol Cell (2001, 8, 1303-1312) copyright 2001.

Figures were selected by an automated process.