PDBsum entry 1fs1

Ligase

PDB id: 1fs1

Contents

Protein chains

41 a.a. *

116 a.a. *

Waters ×570

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Insights into scf ubiquitin ligases from the structure of the skp1-Skp2 complex.

Authors

B.A.Schulman, A.C.Carrano, P.D.Jeffrey, Z.Bowen, E.R.Kinnucan, M.S.Finnin, S.J.Elledge, J.W.Harper, M.Pagano, N.P.Pavletich.

Ref.

Nature, 2000, 408, 381-386. [DOI no: 10.1038/35042620]

PubMed id

11099048

Abstract

F-box proteins are members of a large family that regulates the cell cycle, the immune response, signalling cascades and developmental programmes by targeting proteins, such as cyclins, cyclin-dependent kinase inhibitors, IkappaBalpha and beta-catenin, for ubiquitination (reviewed in refs 1-3). F-box proteins are the substrate-recognition components of SCF (Skp1-Cullin-F-box protein) ubiquitin-protein ligases. They bind the SCF constant catalytic core by means of the F-box motif interacting with Skp1, and they bind substrates through their variable protein-protein interaction domains. The large number of F-box proteins is thought to allow ubiquitination of numerous, diverse substrates. Most organisms have several Skp1 family members, but the function of these Skp1 homologues and the rules of recognition between different F-box and Skp1 proteins remain unknown. Here we describe the crystal structure of the human F-box protein Skp2 bound to Skp1. Skp1 recruits the F-box protein through a bipartite interface involving both the F-box and the substrate-recognition domain. The structure raises the possibility that different Skp1 family members evolved to function with different subsets of F-box proteins, and suggests that the F-box protein may not only recruit substrate, but may also position it optimally for the ubiquitination reaction.

Figure 1.
Figure 1: Structure of the Skp1-Skp2 complex. Skp1 is shown in blue and Skp2 is shown in red. The boundaries of the BTB/POZ fold, the C-terminal helical extension of Skp1 and of the F-box, the three non-canonical LRRs, the seven canonical LRRs and the C-terminal tail of Skp2 are shown in the diagram below the structure. The 100-residue N-terminal Skp2 region missing from the crystallized protein is indicated (dashed line). The second LRR has a partially disordered loop instead of the helix characteristic of LRRs.

Figure 4.
Figure 4: Comparison of the Skp2-Skp1 and VHL-ElonginC-ElonginB complexes. a, Homologous portions of Skp1 and ElonginC are aligned and boxed. Skp2 and VHL are red, Skp1 and ElonginC are blue and ElonginB is green. The LRRs of Skp2 (refs 4, 8, 26, 27) and the -domain of VHL are thought to bind substrate^23. Owing to its unique C terminus, Skp1 binds the F-box differently from the way that ElonginC binds VHL. The arrangement of helices in the two interfaces is similar, although the helices come from non-corresponding members of the complexes (H1 and H2 from VHL superimpose with H6 and H7 from Skp1, not helices from Skp2). b, The ElonginC-binding region of VHL resembles the three-helix cluster structure of the F-box.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2000, 408, 381-386) copyright 2000.