PDBsum entry 1lm8

Transcription

PDB id: 1lm8

Contents

Protein chains

106 a.a. *

88 a.a. *

150 a.a. *

15 a.a. *

Waters ×523

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Structure of an hif-1alpha -Pvhl complex: hydroxyproline recognition in signaling.

Authors

J.H.Min, H.Yang, M.Ivan, F.Gertler, W.G.Kaelin, N.P.Pavletich.

Ref.

Science, 2002, 296, 1886-1889. [DOI no: 10.1126/science.1073440]

PubMed id

12004076

Abstract

The ubiquitination of the hypoxia-inducible factor (HIF) by the von Hippel-Lindau tumor suppressor (pVHL) plays a central role in the cellular response to changes in oxygen availability. pVHL binds to HIF only when a conserved proline in HIF is hydroxylated, a modification that is oxygen-dependent. The 1.85 angstrom structure of a 20-residue HIF-1alpha peptide-pVHL-ElonginB-ElonginC complex shows that HIF-1alpha binds to pVHL in an extended beta strand-like conformation. The hydroxyproline inserts into a gap in the pVHL hydrophobic core, at a site that is a hotspot for tumorigenic mutations, with its 4-hydroxyl group recognized by buried serine and histidine residues. Although the beta sheet-like interactions contribute to the stability of the complex, the hydroxyproline contacts are central to the strict specificity characteristic of signaling.

Figure 1.
Fig. 1. The HIF-1 destruction sequence binds the domain of pVHL in an extended strand-like conformation. (A) Schematic representation of the 15-residue portion of the HIF-1 destruction sequence bound to the domain of pVHL in the pVHL-ElonginB-ElonginC complex. The portion of HIF-1 that adopts a continuous -strand conformation is indicated by a wide arrow. HIF-1 is in blue, Hyp564 in yellow, pVHL in red, ElonginB in magenta, and ElonginC in green. C, COOH-terminus; N, NH[2]-terminus. The figures are prepared with MOLSCRIPT (27), GL_RENDER, and POVRAY (28). (B) Alignment of the first destruction sequence in the ODDs of HIF-1 orthologs and HIF-2 and HIF-3 paralogs, highlighting residues identical in seven of the nine sequences. The N and the C segments of human HIF-1 are indicated in red. The putative N and C segments of the second destruction sequences of HIF-1 and HIF-2 orthologs are aligned below. The reported second destruction sequence is 38 residues long, and only a 23-residue region that aligns with the first destruction sequence is shown. Dashes indicate gaps relative to the seven-residue spacing between the putative N and C segments of the second destruction sequence.

Figure 2.
Fig. 2. The contacts made by the N segment, and in particular by Hyp564, are central to the binding of HIF-1 to pVHL. (A) Closeup view of the HIF-1 N segment-pVHL contacts. The side chains of HIF-1 and pVHL are colored in light blue and yellow, respectively. The backbones of HIF-1 and pVHL are in medium blue and red, respectively. The dotted lines indicate hydrogen bonds between the Gln67 O [1], Tyr98 O , His110 NH, and His110 CO groups of pVHL, and the Leu562 NH, Hyp564 CO, Tyr565 NH, and Tyr565 CO groups of HIF-1 . In pVHL, only the structural elements that make up the HIF-1 binding site are shown for clarity. (B) Surface representation of pVHL colored according to the degree of conservation in the pVHL orthologs in Fig. 1B. Yellow indicates identity in five orthologs (labeled residues), light green in four, and dark green in three. The HIF-1 side chains are in light blue, and the backbone is in medium blue. The N segment is in an orientation similar to that of (A). The approximate boundaries of the N and C segments and of the bulge are indicated. (C) Closeup view of the bulge and the C-segment area of the HIF-1 peptide-pVHL complex. The 567 P-M-D-D 571 bulge sequence does not contact pVHL, but forms an intramolecular -turn hydrogen bond (CO of Pro567 and NH of Asp569). The Asp570 side chain of HIF-1 is omitted for clarity.

The above figures are reprinted by permission from the AAAs: Science (2002, 296, 1886-1889) copyright 2002.