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PDBsum entry 1cf4

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
1cf4
Jmol PyMol
Contents
Protein chains
184 a.a. *
44 a.a. *
Ligands
GNP
Metals
_MG
Waters ×6
* Residue conservation analysis
PDB id:
1cf4
Name: Transferase
Title: Cdc42/ack gtpase-binding domain complex
Structure: Protein (cdc42 homolog). Chain: a. Engineered: yes. Mutation: yes. Protein (activated p21cdc42hs kinase). Chain: b. Fragment: gtpase-binding domain. Other_details: complexed with 5'-guanosyl-imido- triphosphate
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Organism_taxid: 9606
NMR struc: 20 models
Authors: H.R.Mott,D.Owen,D.Nietlispach,P.N.Lowe,L.Lim,E.D.Laue
Key ref:
H.R.Mott et al. (1999). Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK. Nature, 399, 384-388. PubMed id: 10360579 DOI: 10.1038/20732
Date:
23-Mar-99     Release date:   18-Jun-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P60953  (CDC42_HUMAN) -  Cell division control protein 42 homolog
Seq:
Struc:
191 a.a.
184 a.a.*
Protein chain
Pfam  
-  (POLG_HAVHM) - 
Protein chain
Pfam   ArchSchema ?
Q07912  (ACK1_HUMAN) -  Activated CDC42 kinase 1
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1038 a.a.
44 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 2: Chain B: E.C.2.7.10.2  - Non-specific protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
ATP
+ [protein]-L-tyrosine
=
ADP
Bound ligand (Het Group name = GNP)
matches with 78.00% similarity
+ [protein]-L-tyrosine phosphate
   Enzyme class 3: Chain B: E.C.2.7.11.1  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   28 terms 
  Biological process     cardiac conduction system development   82 terms 
  Biochemical function     nucleotide binding     13 terms  

 

 
    reference    
 
 
DOI no: 10.1038/20732 Nature 399:384-388 (1999)
PubMed id: 10360579  
 
 
Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK.
H.R.Mott, D.Owen, D.Nietlispach, P.N.Lowe, E.Manser, L.Lim, E.D.Laue.
 
  ABSTRACT  
 
The proteins Cdc42 and Rac are members of the Rho family of small GTPases (G proteins), which control signal-transduction pathways that lead to rearrangements of the cell cytoskeleton, cell differentiation and cell proliferation. They do so by binding to downstream effector proteins. Some of these, known as CRIB (for Cdc42/Rac interactive-binding) proteins, bind to both Cdc42 and Rac, such as the PAK1-3 serine/threonine kinases, whereas others are specific for Cdc42, such as the ACK tyrosine kinases and the Wiscott-Aldrich-syndrome proteins (WASPs). The effector loop of Cdc42 and Rac (comprising residues 30-40, also called switch I), is one of two regions which change conformation on exchange of GDP for GTP. This region is almost identical in Cdc42 and Racs, indicating that it does not determine the specificity of these G proteins. Here we report the solution structure of the complex of Cdc42 with the GTPase-binding domain ofACK. Both proteins undergo significant conformational changes on binding, to form a new type of G-protein/effector complex. The interaction extends the beta-sheet in Cdc42 by binding an extended strand from ACK, as seen in Ras/effector interactions, but it also involves other regions of the G protein that are important for determining the specificity of effector binding.
 
  Selected figure(s)  
 
Figure 1.
Figure 1: Sequence comparisons, secondary structures and residues involved in complex formation. a, Sequence of the Cdc42-binding domain of the ACK tyrosine kinase, showing the homology to other CRIB-domain proteins. Residues that are conserved in WASP and PAK1, but not in ACK, are boxed. The -helix found in free WASP is indicated by a black line. b, Sequence of Cdc42 compared with that of Rac1. Residues that are different where Cdc42 contacts f-ACK are boxed. The residues comprising switch I and switch II are indicated by black lines. In both a and b, conserved residues involved in the interaction are coloured yellow (hydrophobic), light green (asparagine, glutamine, serine and threonine), red (acidic), magenta (histidine) and dark blue (basic). Blue arrows and grey cylinders indicate the positions of -strands and -helices, respectively, in the Cdc42/f-ACK structure. This Figure was produced with Alscript^28.
Figure 2.
Figure 2: Structure of the Cdc42/f–ACK complex. a, Stereoview of the backbone (C trace) of residues 2–179 of Cdc42 and residues 504–543 of f-ACK from the 20 lowest energy structures (out of 58 that converged from the 100 computed). In the final structures, no distance restraint was violated by more than 0.5 å and no dihedral angle restraint by more than 6.0°. The structures have good covalent geometry and non-bonded contacts (Table 2). b, Representation of the structure closest to the mean in the same orientation as that in a. c, Space-filled representation of the Cdc42/f–ACK complex, showing the hairpin in ACK and the interactions with switch II. f-ACK wraps around Cdc42 forming an extensive interface, burying a surface area of 4,200 å^2 between the two molecules. The structure is rotated 120° about the z -axis compared to b. Figures 2 and 3 were generated using Molscript^29 and Raster3D^30. Cdc42 is in blue and f-ACK is yellow.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (1999, 399, 384-388) copyright 1999.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20535822 A.Sircar, S.Chaudhury, K.P.Kilambi, M.Berrondo, and J.J.Gray (2010).
A generalized approach to sampling backbone conformations with RosettaDock for CAPRI rounds 13-19.
  Proteins, 78, 3115-3123.  
20937872 F.Guo, D.Hildeman, P.Tripathi, C.S.Velu, H.L.Grimes, and Y.Zheng (2010).
Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis.
  Proc Natl Acad Sci U S A, 107, 18505-18510.  
20432460 K.Mahajan, and N.P.Mahajan (2010).
Shepherding AKT and androgen receptor by Ack1 tyrosine kinase.
  J Cell Physiol, 224, 327-333.  
20533885 S.B.Padrick, and M.K.Rosen (2010).
Physical mechanisms of signal integration by WASP family proteins.
  Annu Rev Biochem, 79, 707-735.  
19864426 T.Oda, H.Hashimoto, N.Kuwabara, S.Akashi, K.Hayashi, C.Kojima, H.L.Wong, T.Kawasaki, K.Shimamoto, M.Sato, and T.Shimizu (2010).
Structure of the N-terminal regulatory domain of a plant NADPH oxidase and its functional implications.
  J Biol Chem, 285, 1435-1445.
PDB code: 3a8r
19581296 J.L.Johnson, J.W.Erickson, and R.A.Cerione (2009).
New insights into how the Rho guanine nucleotide dissociation inhibitor regulates the interaction of Cdc42 with membranes.
  J Biol Chem, 284, 23860-23871.  
18394145 A.Hlubek, K.O.Schink, M.Mahlert, B.Sandrock, and M.Bölker (2008).
Selective activation by the guanine nucleotide exchange factor Don1 is a main determinant of Cdc42 signalling specificity in Ustilago maydis.
  Mol Microbiol, 68, 615-623.  
18728011 C.Walliser, M.Retlich, R.Harris, K.L.Everett, M.B.Josephs, P.Vatter, D.Esposito, P.C.Driscoll, M.Katan, P.Gierschik, and T.D.Bunney (2008).
Rac Regulates Its Effector Phospholipase C{gamma}2 through Interaction with a Split Pleckstrin Homology Domain.
  J Biol Chem, 283, 30351-30362.
PDB code: 2k2j
17984089 D.Owen, L.J.Campbell, K.Littlefield, K.A.Evetts, Z.Li, D.B.Sacks, P.N.Lowe, and H.R.Mott (2008).
The IQGAP1-Rac1 and IQGAP1-Cdc42 interactions: interfaces differ between the complexes.
  J Biol Chem, 283, 1692-1704.  
18348980 M.J.Phillips, G.Calero, B.Chan, S.Ramachandran, and R.A.Cerione (2008).
Effector proteins exert an important influence on the signaling-active state of the small GTPase Cdc42.
  J Biol Chem, 283, 14153-14164.
PDB code: 2qrz
17494760 N.P.Mahajan, Y.Liu, S.Majumder, M.R.Warren, C.E.Parker, J.L.Mohler, H.S.Earp, and Y.E.Whang (2007).
Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation.
  Proc Natl Acad Sci U S A, 104, 8438-8443.  
16328953 I.Ahmed, Y.Calle, S.Iwashita, and A.Nur-E-Kamal (2006).
Role of Cdc42 in neurite outgrowth of PC12 cells and cerebellar granule neurons.
  Mol Cell Biochem, 281, 17-25.  
16597700 K.Moissoglu, B.M.Slepchenko, N.Meller, A.F.Horwitz, and M.A.Schwartz (2006).
In vivo dynamics of Rac-membrane interactions.
  Mol Biol Cell, 17, 2770-2779.  
17115053 M.R.Jezyk, J.T.Snyder, S.Gershberg, D.K.Worthylake, T.K.Harden, and J.Sondek (2006).
Crystal structure of Rac1 bound to its effector phospholipase C-beta2.
  Nat Struct Mol Biol, 13, 1135-1140.
PDB code: 2fju
16702216 T.Jank, U.Pack, T.Giesemann, G.Schmidt, and K.Aktories (2006).
Exchange of a single amino acid switches the substrate properties of RhoA and RhoD toward glucosylating and transglutaminating toxins.
  J Biol Chem, 281, 19527-19535.  
16247031 G.Pante, J.Thompson, F.Lamballe, T.Iwata, I.Ferby, F.A.Barr, A.M.Davies, F.Maina, and R.Klein (2005).
Mitogen-inducible gene 6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth.
  J Cell Biol, 171, 337-348.  
16052498 J.M.Ureña, A.La Torre, A.Martínez, E.Lowenstein, N.Franco, R.Winsky-Sommerer, X.Fontana, R.Casaroli-Marano, M.A.Ibáñez-Sabio, M.Pascual, J.A.Del Rio, L.de Lecea, and E.Soriano (2005).
Expression, synaptic localization, and developmental regulation of Ack1/Pyk1, a cytoplasmic tyrosine kinase highly expressed in the developing and adult brain.
  J Comp Neurol, 490, 119-132.  
14999155 A.E.Karnoub, M.Symons, S.L.Campbell, and C.J.Der (2004).
Molecular basis for Rho GTPase signaling specificity.
  Breast Cancer Res Treat, 84, 61-71.  
15653425 E.J.Helmreich (2004).
Structural flexibility of small GTPases. Can it explain their functional versatility?
  Biol Chem, 385, 1121-1136.  
14660612 R.Dvorsky, L.Blumenstein, I.R.Vetter, and M.R.Ahmadian (2004).
Structural insights into the interaction of ROCKI with the switch regions of RhoA.
  J Biol Chem, 279, 7098-7104.
PDB code: 1s1c
15577926 R.Dvorsky, and M.R.Ahmadian (2004).
Always look on the bright site of Rho: structural implications for a conserved intermolecular interface.
  EMBO Rep, 5, 1130-1136.  
12581669 C.Herrmann (2003).
Ras-effector interactions: after one decade.
  Curr Opin Struct Biol, 13, 122-129.  
14514689 D.Owen, P.N.Lowe, D.Nietlispach, C.E.Brosnan, D.Y.Chirgadze, P.J.Parker, T.L.Blundell, and H.R.Mott (2003).
Molecular dissection of the interaction between the small G proteins Rac1 and RhoA and protein kinase C-related kinase 1 (PRK1).
  J Biol Chem, 278, 50578-50587.
PDB code: 1urf
12624092 H.R.Mott, D.Nietlispach, L.J.Hopkins, G.Mirey, J.H.Camonis, and D.Owen (2003).
Structure of the GTPase-binding domain of Sec5 and elucidation of its Ral binding site.
  J Biol Chem, 278, 17053-17059.
PDB code: 1hk6
  12586692 J.Ash, C.Wu, R.Larocque, M.Jamal, W.Stevens, M.Osborne, D.Y.Thomas, and M.Whiteway (2003).
Genetic analysis of the interface between Cdc42p and the CRIB domain of Ste20p in Saccharomyces cerevisiae.
  Genetics, 163, 9.  
12657629 J.T.Snyder, A.U.Singer, M.R.Wing, T.K.Harden, and J.Sondek (2003).
The pleckstrin homology domain of phospholipase C-beta2 as an effector site for Rac.
  J Biol Chem, 278, 21099-21104.  
12409291 M.Endo, M.Shirouzu, and S.Yokoyama (2003).
The Cdc42 binding and scaffolding activities of the fission yeast adaptor protein Scd2.
  J Biol Chem, 278, 843-852.  
12956948 Q.Lin, R.N.Fuji, W.Yang, and R.A.Cerione (2003).
RhoGDI is required for Cdc42-mediated cellular transformation.
  Curr Biol, 13, 1469-1479.  
12606577 S.M.Garrard, C.T.Capaldo, L.Gao, M.K.Rosen, I.G.Macara, and D.R.Tomchick (2003).
Structure of Cdc42 in a complex with the GTPase-binding domain of the cell polarity protein, Par6.
  EMBO J, 22, 1125-1133.
PDB code: 1nf3
12732140 W.D.Heo, and T.Meyer (2003).
Switch-of-function mutants based on morphology classification of Ras superfamily small GTPases.
  Cell, 113, 315-328.  
12009891 H.Garavini, K.Riento, J.P.Phelan, M.S.McAlister, A.J.Ridley, and N.H.Keep (2002).
Crystal structure of the core domain of RhoE/Rnd3: a constitutively activated small G protein.
  Biochemistry, 41, 6303-6310.
PDB code: 1gwn
11997505 K.P.Sem, B.Zahedi, I.Tan, M.Deak, L.Lim, and N.Harden (2002).
ACK family tyrosine kinase activity is a component of Dcdc42 signaling during dorsal closure in Drosophila melanogaster.
  Mol Cell Biol, 22, 3685-3697.  
12202761 Q.Xu, B.Modrek, and C.Lee (2002).
Genome-wide detection of tissue-specific alternative splicing in the human transcriptome.
  Nucleic Acids Res, 30, 3754-3766.  
11900529 R.Thapar, A.E.Karnoub, and S.L.Campbell (2002).
Structural and biophysical insights into the role of the insert region in Rac1 function.
  Biochemistry, 41, 3875-3883.  
11685227 A.E.Karnoub, D.K.Worthylake, K.L.Rossman, W.M.Pruitt, S.L.Campbell, J.Sondek, and C.J.Der (2001).
Molecular basis for Rac1 recognition by guanine nucleotide exchange factors.
  Nat Struct Biol, 8, 1037-1041.  
11294626 A.P.Loh, N.Pawley, L.K.Nicholson, and R.E.Oswald (2001).
An increase in side chain entropy facilitates effector binding: NMR characterization of the side chain methyl group dynamics in Cdc42Hs.
  Biochemistry, 40, 4590-4600.  
11251813 B.Lin, J.M.Skidmore, A.Bhatt, S.M.Pfeffer, L.Pawloski, and J.R.Maddock (2001).
Alanine scan mutagenesis of the switch I domain of the Caulobacter crescentus CgtA protein reveals critical amino acids required for in vivo function.
  Mol Microbiol, 39, 924-934.  
11438672 G.Buchwald, E.Hostinova, M.G.Rudolph, A.Kraemer, A.Sickmann, H.E.Meyer, K.Scheffzek, and A.Wittinghofer (2001).
Conformational switch and role of phosphorylation in PAK activation.
  Mol Cell Biol, 21, 5179-5189.  
11584266 G.Joberty, R.R.Perlungher, P.J.Sheffield, M.Kinoshita, M.Noda, T.Haystead, and I.G.Macara (2001).
Borg proteins control septin organization and are negatively regulated by Cdc42.
  Nat Cell Biol, 3, 861-866.  
11575773 H.Sigel, E.M.Bianchi, N.A.Corfù, Y.Kinjo, R.Tribolet, and R.B.Martin (2001).
Stabilities and isomeric equilibria in solutions of monomeric metal-ion complexes of guanosine 5'-triphosphate (GTP4-) and inosine 5'-triphosphate (ITP4-) in comparison with those of adenosine 5'-triphosphate (ATP4-).
  Chemistry, 7, 3729-3737.  
11701921 I.R.Vetter, and A.Wittinghofer (2001).
The guanine nucleotide-binding switch in three dimensions.
  Science, 294, 1299-1304.  
11738594 K.D.Corbett, and T.Alber (2001).
The many faces of Ras: recognition of small GTP-binding proteins.
  Trends Biochem Sci, 26, 710-716.  
11709168 K.Scheffzek, P.Grünewald, S.Wohlgemuth, W.Kabsch, H.Tu, M.Wigler, A.Wittinghofer, and C.Herrmann (2001).
The Ras-Byr2RBD complex: structural basis for Ras effector recognition in yeast.
  Structure, 9, 1043-1050.
PDB code: 1k8r
11320243 M.Spoerner, C.Herrmann, I.R.Vetter, H.R.Kalbitzer, and A.Wittinghofer (2001).
Dynamic properties of the Ras switch I region and its importance for binding to effectors.
  Proc Natl Acad Sci U S A, 98, 4944-4949.
PDB code: 1iaq
11598009 O.Müller, D.I.Johnson, and A.Mayer (2001).
Cdc42p functions at the docking stage of yeast vacuole membrane fusion.
  EMBO J, 20, 5657-5665.  
10799501 B.C.Böck, P.O.Vacratsis, E.Qamirani, and K.A.Gallo (2000).
Cdc42-induced activation of the mixed-lineage kinase SPRK in vivo. Requirement of the Cdc42/Rac interactive binding motif and changes in phosphorylation.
  J Biol Chem, 275, 14231-14241.  
10799524 B.C.Low, K.T.Seow, and G.R.Guy (2000).
Evidence for a novel Cdc42GAP domain at the carboxyl terminus of BNIP-2.
  J Biol Chem, 275, 14415-14422.  
10747784 D.Gizachew, W.Guo, K.K.Chohan, M.J.Sutcliffe, and R.E.Oswald (2000).
Structure of the complex of Cdc42Hs with a peptide derived from P-21 activated kinase.
  Biochemistry, 39, 3963-3971.
PDB code: 1ees
10684602 D.Owen, H.R.Mott, E.D.Laue, and P.N.Lowe (2000).
Residues in Cdc42 that specify binding to individual CRIB effector proteins.
  Biochemistry, 39, 1243-1250.  
10898977 F.Chen, L.Ma, M.C.Parrini, X.Mao, M.Lopez, C.Wu, P.W.Marks, L.Davidson, D.J.Kwiatkowski, T.Kirchhausen, S.H.Orkin, F.S.Rosen, B.J.Mayer, M.W.Kirschner, and F.W.Alt (2000).
Cdc42 is required for PIP(2)-induced actin polymerization and early development but not for cell viability.
  Curr Biol, 10, 758-765.  
10676816 G.R.Hoffman, N.Nassar, and R.A.Cerione (2000).
Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI.
  Cell, 100, 345-356.
PDB code: 1doa
10966102 G.R.Hoffman, and R.A.Cerione (2000).
Flipping the switch: the structural basis for signaling through the CRIB motif.
  Cell, 102, 403-406.  
11035813 H.G.Vikis, W.Li, Z.He, and K.L.Guan (2000).
The semaphorin receptor plexin-B1 specifically interacts with active Rac in a ligand-dependent manner.
  Proc Natl Acad Sci U S A, 97, 12457-12462.  
  10637312 K.G.Kozminski, A.J.Chen, A.A.Rodal, and D.G.Drubin (2000).
Functions and functional domains of the GTPase Cdc42p.
  Mol Biol Cell, 11, 339-354.  
  11090627 K.Lapouge, S.J.Smith, P.A.Walker, S.J.Gamblin, S.J.Smerdon, and K.Rittinger (2000).
Structure of the TPR domain of p67phox in complex with Rac.GTP.
  Mol Cell, 6, 899-907.
PDB code: 1e96
  11071901 V.M.Braga, M.Betson, X.Li, and N.Lamarche-Vane (2000).
Activation of the small GTPase Rac is sufficient to disrupt cadherin-dependent cell-cell adhesion in normal human keratinocytes.
  Mol Biol Cell, 11, 3703-3721.  
10975523 W.S.Garrett, L.M.Chen, R.Kroschewski, M.Ebersold, S.Turley, S.Trombetta, J.E.Galán, and I.Mellman (2000).
Developmental control of endocytosis in dendritic cells by Cdc42.
  Cell, 102, 325-334.  
10508610 I.Västrik, B.J.Eickholt, F.S.Walsh, A.Ridley, and P.Doherty (1999).
Sema3A-induced growth-cone collapse is mediated by Rac1 amino acids 17-32.
  Curr Biol, 9, 991-998.  
10619026 R.Maesaki, K.Ihara, T.Shimizu, S.Kuroda, K.Kaibuchi, and T.Hakoshima (1999).
The structural basis of Rho effector recognition revealed by the crystal structure of human RhoA complexed with the effector domain of PKN/PRK1.
  Mol Cell, 4, 793-803.
PDB code: 1cxz
10583404 S.Müller, C.von Eichel-Streiber, and M.Moos (1999).
Impact of amino acids 22-27 of Rho-subfamily GTPases on glucosylation by the large clostridial cytotoxins TcsL-1522, TcdB-1470 and TcdB-8864.
  Eur J Biochem, 266, 1073-1080.  
10625453 T.Nomanbhoy, and R.A.Cerione (1999).
Fluorescence assays of Cdc42 interactions with target/effector proteins.
  Biochemistry, 38, 15878-15884.  
10462759 V.Benard, G.M.Bokoch, and B.A.Diebold (1999).
Potential drug targets: small GTPases that regulate leukocyte function.
  Trends Pharmacol Sci, 20, 365-370.  
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.

 

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