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Insights into oncogenic mutations of plexin-B1 based on the solution structure of the Rho GTPase binding domain.

ABSTRACT: The plexin family of transmembrane receptors are important for axon guidance, angiogenesis, but also in cancer. Recently, plexin-B1 somatic missense mutations were found in both primary tumors and metastases of breast and prostate cancers, with several mutations mapping to the Rho GTPase binding domain (RBD) in the cytoplasmic region of the receptor. Here we present the NMR solution structure of this domain, confirming that the protein has both a ubiquitin-like fold and surface features. Oncogenic mutations T1795A and T1802A are located in a loop region, perturb the average structure locally, and have no effect on Rho GTPase binding affinity. Mutations L1815F and L1815P are located at the Rho GTPase binding site and are associated with a complete loss of binding for Rac1 and Rnd1. Both are found to disturb the conformation of the beta3-beta4 sheet and the orientation of surrounding side chains. Our study suggests that the oncogenic behavior of the mutants can be rationalized with reference to the structure of the RBD of plexin-B1.

SUBMITTER: Tong Y

PROVIDER: S-EPMC2358926 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Insights into oncogenic mutations of plexin-B1 based on the solution structure of the Rho GTPase binding domain.

Tong Yufeng Y Hota Prasanta K PK Hamaneh Mehdi Bagheri MB Buck Matthias M

Structure (London, England : 1993) 20080201 2

The plexin family of transmembrane receptors are important for axon guidance, angiogenesis, but also in cancer. Recently, plexin-B1 somatic missense mutations were found in both primary tumors and metastases of breast and prostate cancers, with several mutations mapping to the Rho GTPase binding domain (RBD) in the cytoplasmic region of the receptor. Here we present the NMR solution structure of this domain, confirming that the protein has both a ubiquitin-like fold and surface features. Oncogen ...[more]

PMID: 18275816

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Project description:Plexin-B1 is a single-pass transmembrane receptor. Its Rho GTPase binding domain (RBD) can associate with small Rho GTPases and can also self-bind to form a dimer. In total, more than 400 ns of NAMD molecular dynamics simulations were performed on RBD monomer and dimer. Different analysis methods, such as root mean squared fluctuation (RMSF), order parameters (S(2)), dihedral angle correlation, transfer entropy, principal component analysis, and dynamical network analysis, were carried out to characterize the motions seen in the trajectories. RMSF results show that after binding, the L4 loop becomes more rigid, but the L2 loop and a number of residues in other regions become slightly more flexible. Calculating order parameters (S(2)) for CH, NH, and CO bonds on both backbone and side chain shows that the L4 loop becomes essentially rigid after binding, but part of the L1 loop becomes slightly more flexible. Backbone dihedral angle cross-correlation results show that loop regions such as the L1 loop including residues Q25 and G26, the L2 loop including residue R61, and the L4 loop including residues L89-R91, are highly correlated compared to other regions in the monomer form. Analysis of the correlated motions at these residues, such as Q25 and R61, indicate two signal pathways. Transfer entropy calculations on the RBD monomer and dimer forms suggest that the binding process should be driven by the L4 loop and C-terminal. However, after binding, the L4 loop functions as the motion responder. The signal pathways in RBD were predicted based on a dynamical network analysis method using the pathways predicted from the dihedral angle cross-correlation calculations as input. It is found that the shortest pathways predicted from both inputs can overlap, but signal pathway 2 (from F90 to R61) is more dominant and overlaps all of the routes of pathway 1 (from F90 to P111). This project confirms the allosteric mechanism in signal transmission inside the RBD network, which was in part proposed in the previous experimental study.

Project description:The Plexin family of transmembrane receptors are unique in that their intracellular region interacts directly with small GTPases of the Rho family. The Rho GTPase binding domain of plexin (RBD)-which is responsible for these interactions-can bind with Rac1 as well as Rnd1 GTPases. GTPase complexes have been crystallized with the RBDs of plexinA1, -A2, and -B1. The protein association is thought to elicit different functional responses in a GTPase and plexin isoform specific manner, but the origin of this is unknown. In this project, we investigated complexes between several RBD and Rac1/Rnd1 GTPases using multimicrosecond length all atom molecular dynamics simulations, also with reference to the free forms of the RBDs and GTPases. In accord with the crystallographic data, the RBDs experience more structural changes than Rho-GTPases upon complex formation. Changes in protein dynamics and networks of correlated motions are revealed by analyzing dihedral angle fluctuations in the proteins. The extent of these changes differs between the different RBDs and also between the Rac1 and Rnd1 GTPases. While the RBDs in the free and bound states have similar-if not decreased-correlations, correlations within the GTPases are increased upon binding. Mapping highly correlated residues to the structures, it is found that the plexinA1, -B1, and -A2 RBDs all have similar communication pathways within the ubiquitin fold, but that different residues are involved. Dynamic network analyses indicate that plexinA1 and -B1 RBDs interact with small GTPases in a similar manner, whereas complexes with the plexinA2 RBD display different features. Importantly complexes with Rnd1 have a considerable number of dynamic correlations and network connections between the proteins, whereas such features are missing in the RBD-Rac1 complexes. Overall, the simulations suggest mechanisms that are consistent with the experimental data on plexinB1 and indicate RBD and GTPase isoform specific changes in protein dynamics upon complex formation.

Dataset Information

Insights into oncogenic mutations of plexin-B1 based on the solution structure of the Rho GTPase binding domain.

Publications

Insights into oncogenic mutations of plexin-B1 based on the solution structure of the Rho GTPase binding domain.

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