PDBsum entry 1uus

Signal transduction

PDB id

1uus

Contents

			Protein chain

					465 a.a. *

			Waters ×56

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Structure of an activated dictyostelium stat in its DNA-Unbound form.

Authors

M.Soler-Lopez, C.Petosa, M.Fukuzawa, R.Ravelli, J.G.Williams, C.W.Müller.

Ref.

Mol Cell, 2004, 13, 791-804. [DOI no: 10.1016/S1097-2765(04)00130-3]

PubMed id

15053873

Abstract

Dd-STATa is a STAT protein which transcriptionally regulates cellular differentiation in Dictyostelium discoideum, the only non-metazoan known to employ SH2 domain signaling. The 2.7 A crystal structure of a tyrosine phosphorylated Dd-STATa homodimer reveals a four-domain architecture similar to that of mammalian STATs 1 and 3, but with an inverted orientation for the coiled-coil domain. Dimerization is mediated by SH2 domain:phosphopeptide interactions and by a direct interaction between SH2 domains. The unliganded Dd-STATa dimer adopts a fully extended conformation remarkably different from that of the DNA-bound mammalian STATs, implying a large conformational change upon target site recognition. Buried hydrophilic residues predicted to destabilize the coiled-coil domain suggest how hydrophobic residues may become exposed and mediate nuclear export. Functional and evolutionary implications for metazoan STAT proteins are discussed.



	Figure 3. Figure 3. Structure of the Dimer(A) Side view. The lower monomers of Dd-STATa and STAT3 are viewed as in Figure 2A. Asterisks mark the position of the Asn residue in segment 4 critical for DNA recognition.(B) View along the dyad axis. The STAT3 Ig and EF-hand domains are shown in transparent form. Arrows indicate the chain direction in tail segments.		Figure 4. Figure 4. SH2 Domain and Dimer Interface(A) Comparison of the Dd-STATa (yellow) and STAT3 (green) SH2 domains. The Dd-STATa tail segment is in magenta; that of STAT3 is transparent. The Dd-STATa SH2 domain shares similar sequence identity with the mammalian STATs (18%–22%) as with Src (22%), but a common core of 65 residues is structurally more similar to Src (rmsd[Cα] = 1.13 Å) than to STAT1 (1.27Å) or STAT3 (1.47 Å).(B) Overview of the dimer interface. The view is roughly along the dyad but flipped relative to Figure 3B. The molecular surface and regions of negative (red) and positive (blue) potential are shown for monomer 2. The phosphotyrosine phosphate interacts with three Arg residues (lower right) and is highly buried (upper left). Arg693 is hydrogen bonded to Glu703 and to the backbone carbonyl of Ala695. This figure and Figure 5D were made with GRASP (Nicholls et al., 1991).(C) SH2-P interactions. The view is roughly that of monomer 1 in (B). Hydrogen bonds (dashed lines) are shown in black if common to class I SH2 domains, and in red otherwise. Interactions common to class I domains include phosphotyrosine recognition by Arg594, Arg612, and Ser614; a hydrogen bond between the backbone atoms of His636 (data not shown) and Glu703; and one between Arg594 and the backbone carbonyl of Gly701. Also common is the hydrophobic binding pocket for Leu705 (pY+3), which in Dd-STATa is formed by residues Tyr637, Phe654, His658, and Phe661. Interactions unique to Dd-STATa include those involving Arg616 (see text), a hydrogen bond from Lys635 to the carbonyl of Leu705, a salt bridge between Arg633 and Glu703, and a van der Waals contact between Gln660 and Asn706. For clarity, the side chain of Ser707 is omitted.(D) SH2-SH2 interactions viewed along the dyad axis. Side chains mediating SH2-SH2 contacts are in green (monomer 1) or yellow (monomer 2). Also shown are BG loop residues His658 and Phe661 (in gray) which interact with Leu705, and the hydrogen bond between the backbone of Glu657 and Asn706. For clarity, the side chain of Asn706 is in transparent form, and those of residues 629–630 are omitted.

PROCHECK

	Headers