PDBsum entry 1uoh

Oncoprotein

PDB id: 1uoh

Contents

Protein chain

223 a.a. *

Waters ×115

* Residue conservation analysis

References listed in PDB file

Key reference

Title

The crystal structure of gankyrin, An oncoprotein found in complexes with cyclin-Dependent kinase 4, A 19 s proteasomal atpase regulator, And the tumor suppressors rb and p53.

Authors

S.Krzywda, A.M.Brzozowski, H.Higashitsuji, J.Fujita, R.Welchman, S.Dawson, R.J.Mayer, A.J.Wilkinson.

Ref.

J Biol Chem, 2004, 279, 1541-1545. [DOI no: 10.1074/jbc.M310265200]

PubMed id

14573599

Abstract

Gankyrin is a 25-kDa hepatocellular carcinoma-associated protein that mediates protein-protein interactions in cell cycle control and protein degradation. It has been reported to form complexes with cyclin-dependent kinase 4, retinoblastoma protein, the S6b ATPase subunit of the 19 S regulator of the 26 S proteasome, and Mdm2, an E3 ubiquitin ligase involved in p53 degradation. It is the first protein described to bind both to the 26 S proteasome and to proteins in other complexes containing cyclin-dependent kinase(s) and p53 ubiquitylating activities, thus providing a mechanism for delivering cell cycle regulating machinery and ubiquitylated substrates to the proteasome for degradation. Gankyrin contains a 33-residue motif known as the ankyrin repeat that occurs five and a half to six times in the sequence. As a step toward understanding gankyrin interactions with its protein partners we have determined its three-dimensional crystal structure to 2.0-A resolution. It reveals that the entire 226-residue gankyrin polypeptide folds into seven ankyrin repeat elements. The ankyrin repeats, consisting of an antiparallel beta-hairpin followed by a perpendicularly oriented helix-loop-helix, pack side-by-side, creating an extended curved structure with a groove running across the long concave surface. Comparison with the structures of other ankyrin repeat proteins suggests that interactions with partner proteins are mediated by residues situated on this concave surface.

Figure 1.
FIG. 1. Structure of gankyrin. A, stereo view of the 2F[o] - F[c] electron density maps contoured at the 1 level and displayed on residues 74-78 of ANK2 and 107-111 of ANK3. B-D, orthogonal ribbon representations of gankyrin. The polypeptide chain is color-ramped from its N terminus in blue to the C terminus in red. E, alignment of the five full ankyrin repeat sequences (ANK1-ANK5) together with sequences at the N (ANK0) and C (ANK6) termini of the molecule, which in the structure adopts the ankyrin repeat fold. The schematic below the alignment indicates the span of the -helical and -strand segments of the structure. A consensus ankyrin repeat sequence (16) is shown below the structure. Residues that match the consensus are in blue. F, van der Waals surface representation of gankyrin, with residues colored according to side chain polarity: white, apolar; green, neutral polar; red, acidic; blue, basic. The view is of the concave surface of the molecule in the same orientation as in D.

Figure 4.
FIG. 4. Conformation of LXCXE motifs. Shown is the HPV E7 peptide bound to the pocket domain of Rb (A) and gankyrin (B). In A all the Rb protein atoms are colored in pink with the HPV E7 peptide atoms colored according to element. The Leu, Cys, and Glu side chains of the E7 peptide are buried by their interaction with Rb. In B, gankyrin atoms are colored pink except for those of Leu178, Cys180, and Glu182, which are colored by element. The Cys180 side chain is buried in the protein core.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 1541-1545) copyright 2004.