PRISM: a web server and repository for prediction of protein–protein interactions and modeling their 3D complexes

Baspinar, Alper; Cukuroglu, Engin; Nussinov, Ruth; Keskin, Özlem; Gürsoy, Attila

doi:10.1093/nar/gku397

Cited by 190 publications

(187 citation statements)

References 24 publications

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“…The Ex-mode Cdc42-GRD2 interaction then allosterically releases the C-term and increases its fluctuation to induce GRD2 dimerization. We modelled the Exmode Rac1-GRD2 interaction using PRISM web server, which is a template-based protein-protein interaction prediction tool (39). 500 ns long atomistic MD simulations were performed on the Ex-mode Rac1-GRD2 complex.…”

Section: Cdc42 Insert Loop Binding To the Exdomain Induces Allostericmentioning

confidence: 99%

Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2

Ozdemir

Jang

Gürsoy

et al. 2018

Journal of Biological Chemistry

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IQ motif-containing GTPase-activating protein (IQGAP) scaffolding proteins play central roles in cell-cell adhesion, polarity, and motility. The Rho GTPases Cdc42 and Rac1, in their GTPbound active forms, interact with all three human IQGAPs. The IQGAP-Cdc42 interaction promotes metastasis by enhancing actin polymerization. However, despite their high sequence identity, Cdc42 and Rac1 differ in their interactions with IQGAP. Two Cdc42 molecules can bind to the Exdomain and the RasGAP site of the GTPaseactivating protein (GAP)-related domain (GRD) of IQGAP and promote IQGAP dimerization. Only one Rac1 molecule might bind to the RasGAP site of GRD and may not facilitate the dimerization, and the exact mechanism of Cdc42 and Rac1 binding to IQGAP is unclear. Using all-atom molecular dynamics simulations, site-directed mutagenesis, and Western blotting, we unraveled the detailed mechanisms of Cdc42 and Rac1 interactions with IQGAP2. We observed that Cdc42 binding to the Ex-domain of GRD of IQGAP2 (GRD2) releases the Ex-domain at the C-terminal region of GRD2, facilitating IQGAP2 dimerization. Cdc42 binding to the Ex-domain promoted allosteric changes in the RasGAP site, providing a binding site for the second Cdc42 in the RasGAP site. Of note, the Cdc42 "insert loop" was important for the interaction of the first Cdc42 with the Ex-domain. By contrast, differences in Rac1 insert loop sequence and structure precluded its interaction with the Ex-domain. Rac1 could bind only to the RasGAP site of apo-GRD2 and could not facilitate IQGAP2 dimerization. Our detailed mechanistic insights help decipher how Cdc42 can stimulate actin polymerization in metastasis.The Rho GTPase family is a subfamily of the Ras GTPase superfamily. Rho GTPases regulate multiple cellular processes such as growth, survival, cell invasion, cell motility and vesicle trafficking by interacting with effector molecules (1-4). To date, the mammalian Rho GTPase family includes 22 members; Cdc42, Rac1, and RhoA are the most studied among them (5).Rho GTPases are distinguished from other GTPases by the presence of an "insert loop" which is rich in charged residues in an α-helical motif (Fig. http://www.jbc.org/cgi

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Section: Cdc42 Insert Loop Binding To the Exdomain Induces Allostericmentioning

confidence: 99%

Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2

Ozdemir

Jang

Gürsoy

et al. 2018

Journal of Biological Chemistry

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“…[17][18][19][20] This is a reasonable goal only if the HI comprises a relatively small portion of the entire protein's surface. The majority of HI prediction approaches use machine-learning algorithms and utilize the existing, incomplete library of multimeric structures for training.…”

Section: Introductionmentioning

confidence: 99%

Are protein-protein interfaces special regions on a protein’s surface?

Tonddast-Navaei

Skolnick

2015

The Journal of Chemical Physics

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Protein-protein interactions (PPIs) are involved in many cellular processes. Experimentally obtained protein quaternary structures provide the location of protein-protein interfaces, the surface region of a given protein that interacts with another. These regions are termed half-interfaces (HIs). Canonical HIs cover roughly one third of a protein's surface and were found to have more hydrophobic residues than the non-interface surface region. In addition, the classical view of protein HIs was that there are a few (if not one) HIs per protein that are structurally and chemically unique. However, on average, a given protein interacts with at least a dozen others. This raises the question of whether they use the same or other HIs. By copying HIs from monomers with the same folds in solved quaternary structures, we introduce the concept of geometric HIs (HIs whose geometry has a significant match to other known interfaces) and show that on average they cover three quarters of a protein's surface. We then demonstrate that in some cases, these geometric HI could result in real physical interactions (which may or may not be biologically relevant). The composition of the new HIs is on average more charged compared to most known ones, suggesting that the current protein interface database is biased towards more hydrophobic, possibly more obligate, complexes. Finally, our results provide evidence for interface fuzziness and PPI promiscuity. Thus, the classical view of unique, well defined HIs needs to be revisited as HIs are another example of coarse-graining that is used by nature. C

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“…Binary interactions are predicted by using interface motifs that recur at protein interfaces (Tsai et al, 1996(Tsai et al, , 1997Keskin et al, 2008Keskin et al, , 2016. PRISM is based on these principles and considers recurring motifs in protein interfaces (Tuncbag et al, 2011;Baspinar et al, 2014;Ogmen et al, 2005;Aytuna et al, 2005). In modelling protein assemblies.…”

Section: Introductionmentioning

confidence: 99%

PRISM-EM: template interface-based modelling of multi-protein complexes guided by cryo-electron microscopy density maps

Kuzu

Keskin

Nussinov

et al. 2016

Acta Crystallogr D Struct Biol

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The structures of protein assemblies are important for elucidating cellular processes at the molecular level. Three-dimensional electron microscopy (3DEM) is a powerful method to identify the structures of assemblies, especially those that are challenging to study by crystallography. Here, a new approach, PRISM-EM, is reported to computationally generate plausible structural models using a procedure that combines crystallographic structures and density maps obtained from 3DEM. The predictions are validated against seven available structurally different crystallographic complexes. The models display mean deviations in the backbone of <5 Å . PRISM-EM was further tested on different benchmark sets; the accuracy was evaluated with respect to the structure of the complex, and the correlation with EM density maps and interface predictions were evaluated and compared with those obtained using other methods. PRISM-EM was then used to predict the structure of the ternary complex of the HIV-1 envelope glycoprotein trimer, the ligand CD4 and the neutralizing protein m36.

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PRISM: a web server and repository for prediction of protein–protein interactions and modeling their 3D complexes

Cited by 190 publications

References 24 publications

Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2

Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2

Are protein-protein interfaces special regions on a protein’s surface?

PRISM-EM: template interface-based modelling of multi-protein complexes guided by cryo-electron microscopy density maps

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