PDBsum entry: 1ygs

Tumour suppressor

PDB id: 1ygs

Contents

Protein chain

190 a.a. *

Waters ×138

* Residue conservation analysis

PDB id:

1ygs

Name:

Tumour suppressor

Title:

Crystal structure of the smad4 tumor suppressor c-terminal domain

Structure:

Smad4. Chain: a. Fragment: c-terminal domain, residues 319 - 552. Synonym: dpc4, hmad4, madr4. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Cell_line: bl21 (de3). Cellular_location: cytoplasm (can be translocated into nucleus). Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_cell_line: bl21 (de3).

Biol. unit:

Trimer (from PQS)

Resolution:

2.10Å R-factor: 0.219 R-free: 0.279

Authors:

Y.Shi,A.Hata,R.S.Lo,J.Massague,N.P.Pavletich

Key ref:

Y.Shi et al. (1997). A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature, 388, 87-93. PubMed id: 9214508 DOI: 10.1038/40431

Date:

03-Oct-97 Release date: 08-Jul-98

Protein chain

Q13485  (SMAD4_HUMAN) -  Mothers against decapentaplegic homolog 4

Seq: 552 a.a.

Struc: 190 a.a.

 Gene Ontology (GO) functional annotation 

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

DOI no: 10.1038/40431

Nature 388:87-93 (1997)

PubMed id: 9214508

A structural basis for mutational inactivation of the tumour suppressor Smad4.

Y.Shi, A.Hata, R.S.Lo, J.Massagué, N.P.Pavletich.

ABSTRACT

The Smad4/DPC4 tumour suppressor is inactivated in nearly half of pancreatic carcinomas and to a lesser extent in a variety of other cancers. Smad4/DPC4, and the related tumour suppressor Smad2, belong to the SMAD family of proteins that mediate signalling by the TGF-beta/activin/BMP-2/4 cytokine superfamily from receptor Ser/Thr protein kinases at the cell surface to the nucleus. SMAD proteins, which are phosphorylated by the activated receptor, propagate the signal, in part, through homo- and hetero-oligomeric interactions. Smad4/DPC4 plays a central role as it is the shared hetero-oligomerization partner of the other SMADs. The conserved carboxy-terminal domains of SMADs are sufficient for inducing most of the ligand-specific effects, and are the primary targets of tumorigenic inactivation. We now describe the crystal structure of the C-terminal domain (CTD) of the Smad4/DPC4 tumour suppressor, determined at 2.5 A resolution. The structure reveals that the Smad4/DPC4 CTD forms a crystallographic trimer through a conserved protein-protein interface, to which the majority of the tumour-derived missense mutations map. These mutations disrupt homo-oligomerization in vitro and in vivo, indicating that the trimeric assembly of the Smad4/DPC4 CTD is critical for signalling and is disrupted by tumorigenic mutations.

Selected figure(s)

Figure 1.
Figure 1 The structure of the Smad4/DPC4 CTD consists of a -sandwich with a three-helix bundle on one end and a collection of three large loops and an -helix on the other. The view is along the edge of the -sandwich; the dotted line represents the disordered region between the H3 and H4 helices. Figures were prepared with the programs MOLSCRIPT26 and RASTER3D^27.

Figure 5.
Figure 5 One face of the disk-like trimer structure may mediate hetero-oligomerization. a, Mutations outside the trimer interface map primarily to L3-loop residues, with the exception of Arg 420, which is outside the L3 loop. The face of the trimer shown is opposite to that shown in Fig. 3a. b, Model of hetero-oligomer formation depicting the Smad4/DPC4 and Smad2 CTD trimers as disks. The approximate positions of the Smad4/DPC4 L3 loops and of the Smad2 sites that get phosphorylated by the receptor kinase^30 are shown in yellow and green, respectively.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (1997, 388, 87-93) copyright 1997.

Figures were selected by an automated process.