PDBsum entry 2ovr

Transcription/cell cycle

PDB id: 2ovr

Contents

Protein chains

136 a.a. *

442 a.a. *

Ligands

SER-LEU-ILE-PRO-TPO-PRO-ASP-LYS

SO4 ×12

Waters ×200

* Residue conservation analysis

PDB id:

2ovr

Name:

Transcription/cell cycle

Title:

Structure of the skp1-fbw7-cyclinedegn complex

Structure:

S-phase kinase-associated protein 1a. Chain: a. Fragment: residues 1-147. Synonym: skp1. Cyclin a/cdk2-associated protein p19. P19a. P19skp1. RNA polymerase ii elongation factor-like protein. Organ of corti protein 2. Ocp-ii protein. Ocp-2. Transcription elongation factor b. Siii. Engineered: yes. F-box/wd repeat protein 7.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: skp1a, emc19, ocp2, skp1, tceb1l. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Gene: fbxw7, fbw7, fbx30, sel10. Synthetic: yes. Other_details: sequence occurs naturally in homo sapiens

Resolution:

2.50Å R-factor: 0.225 R-free: 0.251

Authors:

B.Hao,S.Oehlmann,M.E.Sowa,J.W.Harper,N.P.Pavletich

Key ref:

B.Hao et al. (2007). Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases. Mol Cell, 26, 131-143. PubMed id: 17434132 DOI: 10.1016/j.molcel.2007.02.022

Date:

14-Feb-07 Release date: 24-Apr-07

Protein chain

P63208  (SKP1_HUMAN) -  S-phase kinase-associated protein 1 from Homo sapiens

Seq: 163 a.a.

Struc: 136 a.a.

Protein chain

Q969H0  (FBXW7_HUMAN) -  F-box/WD repeat-containing protein 7 from Homo sapiens

Seq: 707 a.a.

Struc: 442 a.a.

DOI no: 10.1016/j.molcel.2007.02.022

Mol Cell 26:131-143 (2007)

PubMed id: 17434132

Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases.

B.Hao, S.Oehlmann, M.E.Sowa, J.W.Harper, N.P.Pavletich.

ABSTRACT

The ubiquitin-mediated proteolysis of cyclin E plays a central role in cell-cycle progression, and cyclin E accumulation is a common event in cancer. Cyclin E degradation is triggered by multisite phosphorylation, which induces binding to the SCF(Fbw7) ubiquitin ligase complex. Structures of the Skp1-Fbw7 complex bound to cyclin E peptides identify a doubly phosphorylated pThr380/pSer384 cyclin E motif as an optimal, high-affinity degron and a singly phosphorylated pThr62 motif as a low-affinity one. Biochemical data indicate that the closely related yeast SCF(Cdc4) complex recognizes the multisite phosphorylated Sic1 substrate similarly and identify three doubly phosphorylated Sic1 degrons, each capable of high-affinity interactions with two Cdc4 phosphate binding sites. A model that explains the role of multiple cyclin E/Sic1 degrons is provided by the findings that Fbw7 and Cdc4 dimerize, that Fbw7 dimerization enhances the turnover of a weakly associated cyclin E in vivo, and that Cdc4 dimerization increases the rate and processivity of Sic1 ubiquitination in vitro.

Selected figure(s)

Figure 1.
Figure 1. Structure of the Skp1-Fbw7-CycE^degC Complex
(A) Overall architecture of the complex, with the secondary structure elements of Skp1, F box, and linker domains labeled. Dotted lines indicate disordered regions.
(B) CycE^degC binds across the narrow face of the Fbw7 β-propeller structure. The eight Fbw7 blades and the strands for one blade are labeled.
(C) Sequence alignment of the cyclin E peptides used in crystallization with other SCF^Fbw7 substrates. Arrow indicates the type II β turn, cylinder the left-handed polyproline II helix, dotted lines disordered regions, and crosses the residues of CycE^degC and CycE^degC that contact Fbw7. The substrate residues that match the structure-based degron motif ( -X- - - -pT/S-P-P-X-pS/T, with representing a hydrophobic residue and X any amino acid) are highlighted in yellow.

Figure 2.
Figure 2. Cyclin E-Fbw7 Contacts in the Skp1-Fbw7-CycE^degC and Skp1-Fbw7-CycE^degN Complexes
(A) Close-up view of the Fbw7-CycE^degC interface showing interacting amino acids of Fbw7 (pink) and CycE^degC (light blue). Hydrogen bonds are shown as white dotted lines. The Fbw7 blade strands that provide cyclin E contacts are labeled.
(B) Close-up view of the Fbw7-CycE^degN interface.
(C) Molecular surface representation of the WD40 domain colored according to conservation among Fbw7 13 orthologs and the Cdc4 and Pop1 homologs (Figure S1).

The above figures are reprinted by permission from Cell Press: Mol Cell (2007, 26, 131-143) copyright 2007.

Figures were selected by an automated process.