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PDBsum entry 2ass
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protein ligands Protein-protein interface(s) links
Cell cycle/ligase/protein turnover PDB id
2ass

 

 

 

 

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Contents
Protein chains
143 a.a. *
325 a.a. *
69 a.a. *
Ligands
PO4 ×3
BEN ×2
Waters ×67
* Residue conservation analysis
PDB id:
2ass
Name: Cell cycle/ligase/protein turnover
Title: Crystal structure of the skp1-skp2-cks1 complex
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. Mutation: 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.
Biol. unit: Trimer (from PQS)
Resolution:
3.00Å     R-factor:   0.214     R-free:   0.242
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    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P63208  (SKP1_HUMAN) -  S-phase kinase-associated protein 1 from Homo sapiens
Seq:
Struc: 		163 a.a.
143 a.a.*
Protein chain
Pfam   ArchSchema ?
Q13309  (SKP2_HUMAN) -  S-phase kinase-associated protein 2 from Homo sapiens
Seq:
Struc: 		424 a.a.
325 a.a.
Protein chain
Pfam   ArchSchema ?
P61024  (CKS1_HUMAN) -  Cyclin-dependent kinases regulatory subunit 1 from Homo sapiens
Seq:
Struc: 		79 a.a.
69 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 

 
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 an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23314863 A.Werner, A.Disanza, N.Reifenberger, G.Habeck, J.Becker, M.Calabrese, H.Urlaub, H.Lorenz, B.Schulman, G.Scita, and F.Melchior (2012).
SCF(Fbxw5) mediates transient degradation of actin remodeller Eps8 to allow proper mitotic progression.
  Nat Cell Biol, 15, 179-188.  
21474069 A.Saha, S.Lewis, G.Kleiger, B.Kuhlman, and R.J.Deshaies (2011).
Essential role for ubiquitin-ubiquitin-conjugating enzyme interaction in ubiquitin discharge from Cdc34 to substrate.
  Mol Cell, 42, 75-83.  
21288713 D.M.Duda, D.C.Scott, M.F.Calabrese, E.S.Zimmerman, N.Zheng, and B.A.Schulman (2011).
Structural regulation of cullin-RING ubiquitin ligase complexes.
  Curr Opin Struct Biol, 21, 257-264.  
19228269 A.Krishnan, S.A.Nair, and M.R.Pillai (2010).
Loss of cks1 homeostasis deregulates cell division cycle.
  J Cell Mol Med, 14, 154-164.  
21172660 I.Ouni, K.Flick, and P.Kaiser (2010).
A transcriptional activator is part of an SCF ubiquitin ligase to control degradation of its cofactors.
  Mol Cell, 40, 954-964.  
  21113395 J.A.Diehl, and B.Ponugoti (2010).
Ubiquitin-dependent proteolysis in G1/S phase control and its relationship with tumor susceptibility.
  Genes Cancer, 1, 717-724.  
20083119 J.Liu, and R.Nussinov (2010).
Molecular dynamics reveal the essential role of linker motions in the function of cullin-RING E3 ligases.
  J Mol Biol, 396, 1508-1523.  
21172649 J.Yan, and Y.Xiong (2010).
Targeted ubiquitylation: the prey becomes predator.
  Mol Cell, 40, 853-855.  
20502441 L.Zhu (2010).
Skp2 knockout reduces cell proliferation and mouse body size: and prevents cancer?
  Cell Res, 20, 605-607.  
19722269 P.Radivojac, V.Vacic, C.Haynes, R.R.Cocklin, A.Mohan, J.W.Heyen, M.G.Goebl, and L.M.Iakoucheva (2010).
Identification, analysis, and prediction of protein ubiquitination sites.
  Proteins, 78, 365-380.  
20516216 R.Holic, A.Kukalev, S.Lane, E.J.Andress, I.Lau, C.W.Yu, M.J.Edelmann, B.M.Kessler, and V.P.Yu (2010).
Cks1 activates transcription by binding to the ubiquitylated proteasome.
  Mol Cell Biol, 30, 3894-3901.  
20067552 R.Hu, and A.E.Aplin (2010).
alphaB-crystallin is mutant B-RAF regulated and contributes to cyclin D1 turnover in melanocytic cells.
  Pigment Cell Melanoma Res, 23, 201-209.  
21036059 S.Desiderio (2010).
Temporal and spatial regulatory functions of the V(D)J recombinase.
  Semin Immunol, 22, 362-369.  
20511590 Y.S.Lo, C.Y.Lin, and J.M.Yang (2010).
PCFamily: a web server for searching homologous protein complexes.
  Nucleic Acids Res, 38, W516-W522.  
19828458 E.B.Askew, S.Bai, A.T.Hnat, J.T.Minges, and E.M.Wilson (2009).
Melanoma antigen gene protein-A11 (MAGE-11) F-box links the androgen receptor NH2-terminal transactivation domain to p160 coactivators.
  J Biol Chem, 284, 34793-34808.  
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.  
19489725 R.J.Deshaies, and C.A.Joazeiro (2009).
RING domain E3 ubiquitin ligases.
  Annu Rev Biochem, 78, 399-434.  
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.  
19744855 T.J.Gibson (2009).
Cell regulation: determined to signal discrete cooperation.
  Trends Biochem Sci, 34, 471-482.  
19584057 W.Zhou, Q.Yang, C.B.Low, B.C.Karthik, Y.Wang, A.Ryo, S.Q.Yao, D.Yang, and Y.C.Liou (2009).
Pin1 catalyzes conformational changes of Thr-187 in p27Kip1 and mediates its stability through a polyubiquitination process.
  J Biol Chem, 284, 23980-23988.  
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.  
18851830 A.Saha, and R.J.Deshaies (2008).
Multimodal activation of the ubiquitin ligase SCF by Nedd8 conjugation.
  Mol Cell, 32, 21-31.  
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.  
18177895 C.A.Galea, A.Nourse, Y.Wang, S.G.Sivakolundu, W.T.Heller, and R.W.Kriwacki (2008).
Role of intrinsic flexibility in signal transduction mediated by the cell cycle regulator, p27 Kip1.
  J Mol Biol, 376, 827-838.  
18805092 D.M.Duda, L.A.Borg, D.C.Scott, H.W.Hunt, M.Hammel, and B.A.Schulman (2008).
Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation.
  Cell, 134, 995.
PDB codes: 3dpl 3dqv
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.  
17434132 B.Hao, S.Oehlmann, M.E.Sowa, J.W.Harper, and N.P.Pavletich (2007).
Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases.
  Mol Cell, 26, 131-143.
PDB codes: 2ovp 2ovq 2ovr
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.  
17933515 P.Knipscheer, and T.K.Sixma (2007).
Protein-protein interactions regulate Ubl conjugation.
  Curr Opin Struct Biol, 17, 665-673.  
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.  
17462724 S.M.Siepka, S.H.Yoo, J.Park, W.Song, V.Kumar, Y.Hu, C.Lee, and J.S.Takahashi (2007).
Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression.
  Cell, 129, 1011-1023.  
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.  
17679094 V.Amador, S.Ge, P.G.Santamaría, D.Guardavaccaro, and M.Pagano (2007).
APC/C(Cdc20) controls the ubiquitin-mediated degradation of p21 in prometaphase.
  Mol Cell, 27, 462-473.  
16473274 A.Koff (2006).
How to decrease p27Kip1 levels during tumor development.
  Cancer Cell, 9, 75-76.  
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 codes are shown on the right.

 

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