PDBsum entry: 1kz7

Signaling protein

PDB-id

1kz7


	Asymmetric unit

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Description

Header details

Protein chains

Waters ×323

* Residue conservation analysis

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		Biological unit, dimer (as deduced by PQS)

PDB id:

1kz7

Name:

Signaling protein

Title:

Crystal structure of the dh/ph fragment of murine dbs in complex with the placental isoform of human cdc42

Structure:

Guanine nucleotide exchange factor dbs. Chain: a, c. Fragment: dh/ph fragment (residues 623-967). Synonym: dbl's big sister, dbs. Engineered: yes. Mutation: yes. Cdc42 homolog. Chain: b, d. Fragment: residues 1-188.

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Gene: dbs. Expressed in: escherichia coli. Expression_system_taxid: 562. Homo sapiens. Human. Organism_taxid: 9606.

Biological unit:

Dimer (from PQS)

UniProt:

Chains A, C: Q64096 (MCF2L_MOUSE)

Seq:

Struc:


Seq:

Struc:


Seq:

Struc:


Seq:

Struc:


Seq:				1149 a.a.

Struc:				337 a.a.*

Chain B: P60953 (CDC42_HUMAN)

Seq:				191 a.a.

Struc:				188 a.a.*

Chain D: P60953 (CDC42_HUMAN)

Seq:

191 a.a.

Struc:

177 a.a.*

Key:		PfamA domain
		Secondary structure			CATH domain

* PDB and UniProt seqs differ at 15 residue positions (black crosses)

Resolution:

2.40Å

R-factor:

0.197

R-free:

0.239

Authors:

K.L.Rossman,D.K.Worthylake,J.T.Snyder,D.P.Siderovski, S.L.Campbell,J.Sondek

Key ref:

K.L.Rossman et al. (2002). A crystallographic view of interactions between Dbs and Cdc42: PH domain-assisted guanine nucleotide exchange.. EMBO J, 21, 1315-1326. [PubMed id: 11889037] [DOI: 10.1093/emboj/21.6.1315]

Date:

06-Feb-02

Release date:

20-Mar-02

Related entries:

1foe
1foe is the crystal structure of the dh/ph fragment of
murine tiam1 in complex with human rac1
1kzg
1kzg is dbscdc42(y889f).

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Key reference

DOI no: 10.1093/emboj/21.6.1315 EMBO J 21:1315-1326 (2002)

PubMed id: 11889037

A crystallographic view of interactions between Dbs and Cdc42: PH domain-assisted guanine nucleotide exchange.

K.L.Rossman, D.K.Worthylake, J.T.Snyder, D.P.Siderovski, S.L.Campbell, J.Sondek.

ABSTRACT

Dbl-related oncoproteins are guanine nucleotide exchange factors (GEFs) specific for Rho guanosine triphosphatases (GTPases) and invariably possess tandem Dbl (DH) and pleckstrin homology (PH) domains. While it is known that the DH domain is the principal catalytic subunit, recent biochemical data indicate that for some Dbl-family proteins, such as Dbs and Trio, PH domains may cooperate with their associated DH domains in promoting guanine nucleotide exchange of Rho GTPases. In order to gain an understanding of the involvement of these PH domains in guanine nucleotide exchange, we have determined the crystal structure of a DH/PH fragment from Dbs in complex with Cdc42. The complex features the PH domain in a unique conformation distinct from the PH domains in the related structures of Sos1 and Tiam1.Rac1. Consequently, the Dbs PH domain participates with the DH domain in binding Cdc42, primarily through a set of interactions involving switch 2 of the GTPase. Comparative sequence analysis suggests that a subset of Dbl-family proteins will utilize their PH domains similarly to Dbs.

Selected figure(s)

Figure 4.
Figure 4 Interactions between the PH domain of Dbs and Cdc42. Stereo view of the PH domain (blue) participating with 6 of the DH domain (yellow) to bind switch 2 (red) and 3b (green) of Cdc42. Dashed lines indicate hydrogen bonds (<3.3Å). Figure 8.
Figure 8 The structure of Dbs Cdc42 suggests a model for membrane engagement.

The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2002, 21, 1315-1326) copyright 2002.

Figures were selected by the author.

Literature references that cite this PDB file's key reference

PubMed id Reference

19759561 S.Demehri, T.O'Hare, C.A.Eide, C.A.Smith, J.W.Tyner, B.J.Druker, and M.W.Deininger (2010).
The function of the pleckstrin homology domain in BCR-ABL-mediated leukemogenesis.

Leukemia, 24, 226-229.

19605563 D.L.Ford-Speelman, J.A.Roche, A.L.Bowman, and R.J.Bloch (2009).
The rho-guanine nucleotide exchange factor domain of obscurin activates rhoA signaling in skeletal muscle.

Mol Biol Cell, 20, 3905-3917.

19670212 T.Cierpicki, J.Bielnicki, M.Zheng, J.Gruszczyk, M.Kasterka, M.Petoukhov, A.Zhang, E.J.Fernandez, D.I.Svergun, U.Derewenda, J.H.Bushweller, and Z.S.Derewenda (2009).
The solution structure and dynamics of the DH-PH module of PDZRhoGEF in isolation and in complex with nucleotide-free RhoA.

Protein Sci, 18, 2067-2079.

19620963 Z.Huang, S.E.Sutton, A.J.Wallenfang, R.C.Orchard, X.Wu, Y.Feng, J.Chai, and N.M.Alto (2009).
Structural insights into host GTPase isoform selection by a family of bacterial GEF mimics.

Nat Struct Mol Biol, 16, 853-860.

PDB code: 3gcg

18378681 C.Mionnet, S.Bogliolo, and R.A.Arkowitz (2008).
Oligomerization regulates the localization of Cdc24, the Cdc42 activator in Saccharomyces cerevisiae.

J Biol Chem, 283, 17515-17530.

18410521 H.Nakanishi, and Y.Takai (2008).
Frabin and other related Cdc42-specific guanine nucleotide exchange factors couple the actin cytoskeleton with the plasma membrane.

J Cell Mol Med, 12, 1169-1176.

18511940 J.Rapley, V.L.Tybulewicz, and K.Rittinger (2008).
Crucial structural role for the PH and C1 domains of the Vav1 exchange factor.

EMBO Rep, 9, 655-661.

PDB code: 2vrw

18056264 M.A.Kwofie, and J.Skowronski (2008).
Specific Recognition of Rac2 and Cdc42 by DOCK2 and DOCK9 Guanine Nucleotide Exchange Factors.

J Biol Chem, 283, 3088-3096.

18541910 T.K.Smith, H.A.Hager, R.Francis, D.M.Kilkenny, C.W.Lo, and D.M.Bader (2008).
Bves directly interacts with GEFT, and controls cell shape and movement through regulation of Rac1/Cdc42 activity.

Proc Natl Acad Sci U S A, 105, 8298-8303.

18505730 Y.Ugolev, Y.Berdichevsky, C.Weinbaum, and E.Pick (2008).
Dissociation of Rac1(GDP).RhoGDI complexes by the cooperative action of anionic liposomes containing phosphatidylinositol 3,4,5-trisphosphate, Rac guanine nucleotide exchange factor, and GTP.

J Biol Chem, 283, 22257-22271.

17847065 A.Bottani, A.Orrico, L.Galli, O.Karam, C.A.Haenggeli, S.Ferey, and B.Conrad (2007).
Unilateral focal polymicrogyria in a patient with classical Aarskog-Scott syndrome due to a novel missense mutation in an evolutionary conserved RhoGEF domain of the faciogenital dysplasia gene FGD1.

Am J Med Genet A, 143, 2334-2338.

17601877 A.G.Howe, G.D.Fairn, K.MacDonald, V.A.Bankaitis, and C.R.McMaster (2007).
Regulation of phosphoinositide levels by the phospholipid transfer protein Sec14p controls Cdc42p/p21-activated kinase-mediated cell cycle progression at cytokinesis.

Eukaryot Cell, 6, 1814-1823.

17984318 C.Frantz, A.Karydis, P.Nalbant, K.M.Hahn, and D.L.Barber (2007).
Positive feedback between Cdc42 activity and H+ efflux by the Na-H exchanger NHE1 for polarity of migrating cells.

J Cell Biol, 179, 403-410.

17581628 G.Zhu, J.Chen, J.Liu, J.S.Brunzelle, B.Huang, N.Wakeham, S.Terzyan, X.Li, Z.Rao, G.Li, and X.C.Zhang (2007).
Structure of the APPL1 BAR-PH domain and characterization of its interaction with Rab5.

EMBO J, 26, 3484-3493.

PDB codes: 2q12 2q13

17264933 J.M.Davis, L.K.Tsou, and A.D.Hamilton (2007).
Synthetic non-peptide mimetics of alpha-helices.

Chem Soc Rev, 36, 326-334.

17214551 K.Gotthardt, and M.R.Ahmadian (2007).
Asef is a Cdc42-specific guanine nucleotide exchange factor.

Biol Chem, 388, 67-71.

17190834 K.Murayama, M.Shirouzu, Y.Kawasaki, M.Kato-Murayama, K.Hanawa-Suetsugu, A.Sakamoto, Y.Katsura, A.Suenaga, M.Toyama, T.Terada, M.Taiji, T.Akiyama, and S.Yokoyama (2007).
Crystal structure of the rac activator, Asef, reveals its autoinhibitory mechanism.

J Biol Chem, 282, 4238-4242.

PDB code: 2dx1

17803212 K.Wiehe, B.Pierce, W.W.Tong, H.Hwang, J.Mintseris, and Z.Weng (2007).
The performance of ZDOCK and ZRANK in rounds 6-11 of CAPRI.

Proteins, 69, 719-725.

17337446 M.E.Yohe, K.L.Rossman, O.S.Gardner, A.E.Karnoub, J.T.Snyder, S.Gershburg, L.M.Graves, C.J.Der, and J.Sondek (2007).
Auto-inhibition of the Dbl family protein Tim by an N-terminal helical motif.

J Biol Chem, 282, 13813-13823.

17391702 M.K.Chhatriwala, L.Betts, D.K.Worthylake, and J.Sondek (2007).
The DH and PH domains of Trio coordinately engage Rho GTPases for their efficient activation.

J Mol Biol, 368, 1307-1320.

PDB code: 2nz8

17606614 R.J.Rojas, M.E.Yohe, S.Gershburg, T.Kawano, T.Kozasa, and J.Sondek (2007).
Galphaq directly activates p63RhoGEF and Trio via a conserved extension of the Dbl homology-associated pleckstrin homology domain.

J Biol Chem, 282, 29201-29210.

17392278 U.E.Rennefahrt, S.W.Deacon, S.A.Parker, K.Devarajan, A.Beeser, J.Chernoff, S.Knapp, B.E.Turk, and J.R.Peterson (2007).
Specificity profiling of Pak kinases allows identification of novel phosphorylation sites.

J Biol Chem, 282, 15667-15678.

16954208 A.Oleksy, �.�.Opaliński, U.Derewenda, Z.S.Derewenda, and J.Otlewski (2006).
The molecular basis of RhoA specificity in the guanine nucleotide exchange factor PDZ-RhoGEF.

J Biol Chem, 281, 32891-32897.

16408091 H.E.Pelish, J.R.Peterson, S.B.Salvarezza, E.Rodriguez-Boulan, J.L.Chen, M.Stamnes, E.Macia, Y.Feng, M.D.Shair, and T.Kirchhausen (2006).
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Nat Chem Biol, 2, 39-46.

16632257 J.R.Peterson, A.M.Lebensohn, H.E.Pelish, and M.W.Kirschner (2006).
Biochemical suppression of small-molecule inhibitors: a strategy to identify inhibitor targets and signaling pathway components.

Chem Biol, 13, 443-452.

17051233 K.E.Ile, G.Schaaf, and V.A.Bankaitis (2006).
Phosphatidylinositol transfer proteins and cellular nanoreactors for lipid signaling.

Nat Chem Biol, 2, 576-583.

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.

16613852 Z.Liu, E.V.Kostenko, G.M.Mahon, O.O.Olabisi, and I.P.Whitehead (2006).
Transformation by the Rho-specific guanine nucleotide exchange factor Dbs requires ROCK I-mediated phosphorylation of myosin light chain.

J Biol Chem, 281, 16043-16051.

15758069 J.Yamauchi, J.R.Chan, Y.Miyamoto, G.Tsujimoto, and E.M.Shooter (2005).
The neurotrophin-3 receptor TrkC directly phosphorylates and activates the nucleotide exchange factor Dbs to enhance Schwann cell migration.

Proc Natl Acad Sci U S A, 102, 5198-5203.

15688002 K.L.Rossman, C.J.Der, and J.Sondek (2005).
GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors.

Nat Rev Mol Cell Biol, 6, 167-180.

15775967 O.Llorca, E.Arias-Palomo, J.L.Zugaza, and X.R.Bustelo (2005).
Global conformational rearrangements during the activation of the GDP/GTP exchange factor Vav3.

EMBO J, 24, 1330-1340.

15897194 R.E.Joseph, and F.A.Norris (2005).
Substrate specificity and recognition is conferred by the pleckstrin homology domain of the Dbl family guanine nucleotide exchange factor P-Rex2.

J Biol Chem, 280, 27508-27512.

15107860 A.Godi, A.Di Campli, A.Konstantakopoulos, G.Di Tullio, D.R.Alessi, G.S.Kular, T.Daniele, P.Marra, J.M.Lucocq, and M.A.De Matteis (2004).
FAPPs control Golgi-to-cell-surface membrane traffic by binding to ARF and PtdIns(4)P.

Nat Cell Biol, 6, 393-404.

15039571 A.Oleksy, H.Barton, Y.Devedjiev, M.Purdy, U.Derewenda, J.Otlewski, and Z.S.Derewenda (2004).
Preliminary crystallographic analysis of the complex of the human GTPase RhoA with the DH/PH tandem of PDZ-RhoGEF.

Acta Crystallogr D Biol Crystallogr, 60, 740-742.

15271978 A.Roy, and T.P.Levine (2004).
Multiple pools of phosphatidylinositol 4-phosphate detected using the pleckstrin homology domain of Osh2p.

J Biol Chem, 279, 44683-44689.

14597635 B.Debreceni, Y.Gao, F.Guo, K.Zhu, B.Jia, and Y.Zheng (2004).
Mechanisms of guanine nucleotide exchange and Rac-mediated signaling revealed by a dominant negative trio mutant.

J Biol Chem, 279, 3777-3786.

15169787 D.Auguin, P.Barthe, C.Royer, M.H.Stern, M.Noguchi, S.T.Arold, and C.Roumestand (2004).
Structural basis for the co-activation of protein kinase B by T-cell leukemia-1 (TCL1) family proto-oncoproteins.

J Biol Chem, 279, 35890-35902.

15355962 K.Grohmanova, D.Schlaepfer, D.Hess, P.Gutierrez, M.Beck, and R.Kroschewski (2004).
Phosphorylation of IQGAP1 modulates its binding to Cdc42, revealing a new type of rho-GTPase regulator.

J Biol Chem, 279, 48495-48504.

15199069 K.R.Skowronek, F.Guo, Y.Zheng, and N.Nassar (2004).
The C-terminal basic tail of RhoG assists the guanine nucleotide exchange factor trio in binding to phospholipids.

J Biol Chem, 279, 37895-37907.

PDB code: 1nty

14701795 L.Cheng, G.M.Mahon, E.V.Kostenko, and I.P.Whitehead (2004).
Pleckstrin homology domain-mediated activation of the rho-specific guanine nucleotide exchange factor Dbs by Rac1.

J Biol Chem, 279, 12786-12793.

15247908 M.Lu, J.M.Kinchen, K.L.Rossman, C.Grimsley, C.deBakker, E.Brugnera, A.C.Tosello-Trampont, L.B.Haney, D.Klingele, J.Sondek, M.O.Hengartner, and K.S.Ravichandran (2004).
PH domain of ELMO functions in trans to regulate Rac activation via Dock180.

Nat Struct Mol Biol, 11, 756-762.

15247287 N.Meller, M.Irani-Tehrani, B.I.Ratnikov, B.M.Paschal, and M.A.Schwartz (2004).
The novel Cdc42 guanine nucleotide exchange factor, zizimin1, dimerizes via the Cdc42-binding CZH2 domain.

J Biol Chem, 279, 37470-37476.

15073184 P.A.Solski, R.S.Wilder, K.L.Rossman, J.Sondek, A.D.Cox, S.L.Campbell, and C.J.Der (2004).
Requirement for C-terminal sequences in regulation of Ect2 guanine nucleotide exchange specificity and transformation.

J Biol Chem, 279, 25226-25233.

15306850 Q.Feng, D.Baird, and R.A.Cerione (2004).
Novel regulatory mechanisms for the Dbl family guanine nucleotide exchange factor Cool-2/alpha-Pix.

EMBO J, 23, 3492-3504.

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.

15331592 R.Kristelly, G.Gao, and J.J.Tesmer (2004).
Structural determinants of RhoA binding and nucleotide exchange in leukemia-associated Rho guanine-nucleotide exchange factor.

J Biol Chem, 279, 47352-47362.

PDB codes: 1txd 1x86

15302837 S.Barale, D.McCusker, and R.A.Arkowitz (2004).
The exchange factor Cdc24 is required for cell fusion during yeast mating.

Eukaryot Cell, 3, 1049-1061.

15128949 Y.Gao, J.B.Dickerson, F.Guo, J.Zheng, and Y.Zheng (2004).
Rational design and characterization of a Rac GTPase-specific small molecule inhibitor.

Proc Natl Acad Sci U S A, 101, 7618-7623.

12637530 E.J.Fuentes, A.E.Karnoub, M.A.Booden, C.J.Der, and S.L.Campbell (2003).
Critical role of the pleckstrin homology domain in Dbs signaling and growth regulation.

J Biol Chem, 278, 21188-21196.

12885767 G.E.Cozier, D.Bouyoucef, and P.J.Cullen (2003).
Engineering the phosphoinositide-binding profile of a class I pleckstrin homology domain.

J Biol Chem, 278, 39489-39496.

12637522 K.L.Rossman, L.Cheng, G.M.Mahon, R.J.Rojas, J.T.Snyder, I.P.Whitehead, and J.Sondek (2003).
Multifunctional roles for the PH domain of Dbs in regulating Rho GTPase activation.

J Biol Chem, 278, 18393-18400.

12471028 K.Robbe, A.Otto-Bruc, P.Chardin, and B.Antonny (2003).
Dissociation of GDP dissociation inhibitor and membrane translocation are required for efficient activation of Rac by the Dbl homology-pleckstrin homology region of Tiam.

J Biol Chem, 278, 4756-4762.

12832783 K.Skowronek, M.Ghumman, Y.Zheng, and N.Nassar (2003).
Crystallization and initial crystal characterization of the N-terminal DH/PH domain of Trio.

Acta Crystallogr D Biol Crystallogr, 59, 1273-1275.

12525493 M.A.Baumeister, L.Martinu, K.L.Rossman, J.Sondek, M.A.Lemmon, and M.M.Chou (2003).
Loss of phosphatidylinositol 3-phosphate binding by the C-terminal Tiam-1 pleckstrin homology domain prevents in vivo Rac1 activation without affecting membrane targeting.

J Biol Chem, 278, 11457-11464.

12719429 M.C.Schlumberger, A.Friebel, G.Buchwald, K.Scheffzek, A.Wittinghofer, and W.D.Hardt (2003).
Amino acids of the bacterial toxin SopE involved in G nucleotide exchange on Cdc42.

J Biol Chem, 278, 27149-27159.

14501138 R.Kristelly, B.T.Earnest, L.Krishnamoorthy, and J.J.Tesmer (2003).
Preliminary structure analysis of the DH/PH domains of leukemia-associated RhoGEF.

Acta Crystallogr D Biol Crystallogr, 59, 1859-1862.

12972602 T.J.Kubiseski, J.Culotti, and T.Pawson (2003).
Functional analysis of the Caenorhabditis elegans UNC-73B PH domain demonstrates a role in activation of the Rac GTPase in vitro and axon guidance in vivo.

Mol Cell Biol, 23, 6823-6835.

12093730 G.Buchwald, A.Friebel, J.E.Galán, W.D.Hardt, A.Wittinghofer, and K.Scheffzek (2002).
Structural basis for the reversible activation of a Rho protein by the bacterial toxin SopE.

EMBO J, 21, 3286-3295.

PDB code: 1gzs

12006984 J.T.Snyder, D.K.Worthylake, K.L.Rossman, L.Betts, W.M.Pruitt, D.P.Siderovski, C.J.Der, and J.Sondek (2002).
Structural basis for the selective activation of Rho GTPases by Dbl exchange factors.

Nat Struct Biol, 9, 468-475.

PDB codes: 1ki1 1lb1

12401782 K.L.Rossman, D.K.Worthylake, J.T.Snyder, L.Cheng, I.P.Whitehead, and J.Sondek (2002).
Functional analysis of cdc42 residues required for Guanine nucleotide exchange.

J Biol Chem, 277, 50893-50898.

12215546 L.Cheng, K.L.Rossman, G.M.Mahon, D.K.Worthylake, M.Korus, J.Sondek, and I.P.Whitehead (2002).
RhoGEF specificity mutants implicate RhoA as a target for Dbs transforming activity.

Mol Cell Biol, 22, 6895-6905.

12177050 T.R.Palmby, K.Abe, and C.J.Der (2002).
Critical role of the pleckstrin homology and cysteine-rich domains in Vav signaling and transforming activity.

J Biol Chem, 277, 39350-39359.

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.