PDBsum entry: 2ast

Cell cycle/ligase/protein turnover

PDB-id

2ast


	Asymmetric unit

Contents

Description

Header details

Protein chains

Ligands

ALA-GLY-SER-VAL-
GLU-GLN-TPO-PRO-
LYS-LYS

BEN ×2

Waters ×265

* Residue conservation analysis

Tools

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Clefts Calculation

		Biological unit, tetramer (as deduced by PQS)

PDB id:

2ast

Name:

Cell cycle/ligase/protein turnover

Title:

Crystal structure of skp1-skp2-cks1 in complex with a p27 peptide

Structure:

S-phase kinase-associated protein 1a. Chain: a. Synonym: 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. S-phase kinase-associated protein 2. Chain: b.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: skp1a, emc19, ocp2, skp1, tceb1l. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: skp2, fbxl1. Gene: cks1, cks1b. Synthetic: yes.

Biological unit:

Tetramer (from PQS)

UniProt:

Chain A: P63208 (SKP1_HUMAN)

Seq:				163 a.a.

Struc:				142 a.a.*

Chain B: Q13309 (SKP2_HUMAN)

Seq:

Struc:


Seq:				424 a.a.

Struc:				325 a.a.

Chain C: P61024 (CKS1_HUMAN)

Seq:

79 a.a.

Struc:

69 a.a.

Key:		PfamA domain			PfamB domain
		Secondary structure			CATH domain

* PDB and UniProt seqs differ at 1 residue position (black cross)

Resolution:

2.30Å

R-factor:

0.203

R-free:

0.221

Authors:

B.Hao,N.Zhang,B.A.Schulman,G.Wu,M.Pagano,N.P.Pavletich

Key ref:

B.Hao et al. (2005). Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase.. Mol Cell, 20, 9. [PubMed id: 16209941] [DOI: 10.1016/j.molcel.2005.09.003]

Date:

24-Aug-05

Release date:

18-Oct-05

Related entries:

2ass
crystal structure of the skp1-skp2-cks1 complex
1fqv
crystal structure of skp1-skp2

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Key reference

DOI no: 10.1016/j.molcel.2005.09.003 Mol Cell 20:9 (2005)

PubMed id: 16209941

Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase.

B.Hao, N.Zheng, B.A.Schulman, G.Wu, J.J.Miller, M.Pagano, N.P.Pavletich.

ABSTRACT

The ubiquitin-mediated proteolysis of the Cdk2 inhibitor p27(Kip1) plays a central role in cell cycle progression, and enhanced degradation of p27(Kip1) is associated with many common cancers. Proteolysis of p27(Kip1) is triggered by Thr187 phosphorylation, which leads to the binding of the SCF(Skp2) (Skp1-Cul1-Rbx1-Skp2) ubiquitin ligase complex. Unlike other known SCF substrates, p27(Kip1) ubiquitination also requires the accessory protein Cks1. The crystal structure of the Skp1-Skp2-Cks1 complex bound to a p27(Kip1) phosphopeptide shows that Cks1 binds to the leucine-rich repeat (LRR) domain and C-terminal tail of Skp2, whereas p27(Kip1) binds to both Cks1 and Skp2. The phosphorylated Thr187 side chain of p27(Kip1) is recognized by a Cks1 phosphate binding site, whereas the side chain of an invariant Glu185 inserts into the interface between Skp2 and Cks1, interacting with both. The structure and biochemical data support the proposed model that Cdk2-cyclin A contributes to the recruitment of p27(Kip1) to the SCF(Skp2)-Cks1 complex.

Selected figure(s)

Figure 2.
Figure 2. Structure of the Skp1-Skp2-Cks1-p27^Kip1 Complex Figure 3.
Figure 3. Intermolecular Contacts in the Skp1-Skp2-Cks1-p27^Kip1 Complex

The above figures are reprinted by permission from Cell Press: Mol Cell (2005, 20, 9-0) copyright 2005.

Figures were selected by the author.

Literature references that cite this PDB file's key reference

PubMed id Reference

19798438 J.Liu, and R.Nussinov (2009).
The mechanism of ubiquitination in the cullin-RING E3 ligase machinery: conformational control of substrate orientation.

PLoS Comput Biol, 5, e1000527.

19264588 S.Sonnberg, S.B.Fleming, and A.A.Mercer (2009).
A truncated two-{alpha}-helix F-box present in poxvirus ankyrin-repeat proteins is sufficient for binding the SCF1 ubiquitin ligase complex.

J Gen Virol, 90, 1224-1228.

19050175 X.Tan, and N.Zheng (2009).
Hormone signaling through protein destruction: a lesson from plants.

Am J Physiol Endocrinol Metab, 296, E223-E227.

18559973 A.Agarwal, T.G.Bumm, A.S.Corbin, T.O'Hare, M.Loriaux, J.VanDyke, S.G.Willis, J.Deininger, K.I.Nakayama, B.J.Druker, and M.W.Deininger (2008).
Absence of SKP2 expression attenuates BCR-ABL-induced myeloproliferative disease.

Blood, 112, 1960-1970.

18301771 A.V.Kajava, M.Anisimova, and N.Peeters (2008).
Origin and evolution of GALA-LRR, a new member of the CC-LRR subfamily: from plants to bacteria?

PLoS ONE, 3, e1694.

18625720 H.S.Martinsson-Ahlzén, V.Liberal, B.Grünenfelder, S.R.Chaves, C.H.Spruck, and S.I.Reed (2008).
Cyclin-dependent kinase-associated proteins Cks1 and Cks2 are essential during early embryogenesis and for cell cycle progression in somatic cells.

Mol Cell Biol, 28, 5698-5709.

18818696 M.Zhang, M.Botër, K.Li, Y.Kadota, B.Panaretou, C.Prodromou, K.Shirasu, and L.H.Pearl (2008).
Structural and functional coupling of Hsp90- and Sgt1-centred multi-protein complexes.

EMBO J, 27, 2789-2798.

PDB code: 2jki

18305219 Q.Chen, W.Xie, D.J.Kuhn, P.M.Voorhees, A.Lopez-Girona, D.Mendy, L.G.Corral, V.P.Krenitsky, W.Xu, L.Moutouh-de Parseval, D.R.Webb, F.Mercurio, K.I.Nakayama, K.Nakayama, and R.Z.Orlowski (2008).
Targeting the p27 E3 ligase SCF(Skp2) results in p27- and Skp2-mediated cell-cycle arrest and activation of autophagy.

Blood, 111, 4690-4699.

18214954 Q.R.Fan, and W.A.Hendrickson (2008).
Comparative structural analysis of the binding domain of follicle stimulating hormone receptor.

Proteins, 72, 393-401.

18698327 T.Ravid, and M.Hochstrasser (2008).
Diversity of degradation signals in the ubiquitin-proteasome system.

Nat Rev Mol Cell Biol, 9, 679-690.

17477837 B.T.Dye, and B.A.Schulman (2007).
Structural mechanisms underlying posttranslational modification by ubiquitin-like proteins.

Annu Rev Biophys Biomol Struct, 36, 131-150.

16924675 C.A.Auld, C.D.Caccia, and R.F.Morrison (2007).
Hormonal induction of adipogenesis induces Skp2 expression through PI3K and MAPK pathways.

J Cell Biochem, 100, 204-216.

17096381 C.A.Auld, K.M.Fernandes, and R.F.Morrison (2007).
Skp2-mediated p27(Kip1) degradation during S/G2 phase progression of adipocyte hyperplasia.

J Cell Physiol, 211, 101-111.

17439941 E.H.Chew, and T.Hagen (2007).
Substrate-mediated regulation of cullin neddylation.

J Biol Chem, 282, 17032-17040.

17892493 G.Lippens, I.Landrieu, and C.Smet (2007).
Molecular mechanisms of the phospho-dependent prolyl cis/trans isomerase Pin1.

FEBS J, 274, 5211-5222.

17785450 K.Umanskaya, S.Radke, H.Chander, R.Monardo, X.Xu, Z.Q.Pan, M.J.O'Connell, and D.Germain (2007).
Skp2B stimulates mammary gland development by inhibiting REA, the repressor of the estrogen receptor.

Mol Cell Biol, 27, 7615-7622.

16924241 K.V.Bhatt, R.Hu, L.S.Spofford, and A.E.Aplin (2007).
Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells.

Oncogene, 26, 1056-1066.

17517123 N.Matsushima, T.Tanaka, P.Enkhbayar, T.Mikami, M.Taga, K.Yamada, and Y.Kuroki (2007).
Comparative sequence analysis of leucine-rich repeats (LRRs) within vertebrate toll-like receptors.

BMC Genomics, 8, 124.

17224055 O.Barbash, D.I.Lin, and J.A.Diehl (2007).
SCF Fbx4/alphaB-crystallin cyclin D1 ubiquitin ligase: a license to destroy.

Cell Div, 2, 2.

18419282 S.M.Siepka, S.H.Yoo, J.Park, C.Lee, and J.S.Takahashi (2007).
Genetics and neurobiology of circadian clocks in mammals.

Cold Spring Harb Symp Quant Biol, 72, 251-259.

17409098 S.Xu, M.Abbasian, P.Patel, K.Jensen-Pergakes, C.R.Lombardo, B.E.Cathers, W.Xie, F.Mercurio, M.Pagano, D.Giegel, and S.Cox (2007).
Substrate recognition and ubiquitination of SCFSkp2/Cks1 ubiquitin-protein isopeptide ligase.

J Biol Chem, 282, 15462-15470.

18047746 T.Cardozo, and M.Pagano (2007).
Wrenches in the works: drug discovery targeting the SCF ubiquitin ligase and APC/C complexes.

BMC Biochem, 8, S9.

17389369 T.Mizushima, Y.Yoshida, T.Kumanomidou, Y.Hasegawa, A.Suzuki, T.Yamane, and K.Tanaka (2007).
Structural basis for the selection of glycosylated substrates by SCF(Fbs1) ubiquitin ligase.

Proc Natl Acad Sci U S A, 104, 5777-5781.

PDB codes: 2e31 2e32 2e33

17907805 T.Munakata, Y.Liang, S.Kim, D.R.McGivern, J.Huibregtse, A.Nomoto, and S.M.Lemon (2007).
Hepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein.

PLoS Pathog, 3, 1335-1347.

17464290 U.B.Keller, J.B.Old, F.C.Dorsey, J.A.Nilsson, L.Nilsson, K.H.MacLean, L.Chung, C.Yang, C.Spruck, K.Boyd, S.I.Reed, and J.L.Cleveland (2007).
Myc targets Cks1 to provoke the suppression of p27Kip1, proliferation and lymphomagenesis.

EMBO J, 26, 2562-2574.

17189539 C.A.Auld, and R.F.Morrison (2006).
Evidence for cytosolic p27(Kip1) ubiquitylation and degradation during adipocyte hyperplasia.

Obesity (Silver Spring), 14, 2136-2144.

17081987 D.I.Lin, O.Barbash, K.G.Kumar, J.D.Weber, J.W.Harper, A.J.Klein-Szanto, A.Rustgi, S.Y.Fuchs, and J.A.Diehl (2006).
Phosphorylation-dependent ubiquitination of cyclin D1 by the SCF(FBX4-alphaB crystallin) complex.

Mol Cell, 24, 355-366.

16816840 G.Nalepa, M.Rolfe, and J.W.Harper (2006).
Drug discovery in the ubiquitin-proteasome system.

Nat Rev Drug Discov, 5, 596-613.

16774918 P.Ji, L.Goldin, H.Ren, D.Sun, D.Guardavaccaro, M.Pagano, and L.Zhu (2006).
Skp2 contains a novel cyclin A binding domain that directly protects cyclin A from inhibition by p27Kip1.

J Biol Chem, 281, 24058-24069.

16925947 Y.Sun (2006).
E3 ubiquitin ligases as cancer targets and biomarkers.

Neoplasia, 8, 645-654.

16771627 Z.Liu, and R.A.Butow (2006).
Mitochondrial retrograde signaling.

Annu Rev Genet, 40, 159-185.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.