Dataset Information

PDE? Binding to Ras Isoforms Provides a Route to Proper Membrane Localization.

ABSTRACT: To signal, Ras isoforms must be enriched at the plasma membrane (PM). It was suggested that phosphodiesterase-? (PDE?) can bind and shuttle some farnesylated Ras isoforms to the PM, but not all. Among these, interest focused on K-Ras4B, the most abundant oncogenic Ras isoform. To study PDE?/Ras interactions, we modeled and simulated the PDE?/K-Ras4B complex. We obtained structures, which were similar to two subsequently determined crystal structures. We next modeled and simulated complexes of PDE? with the farnesylated hypervariable regions of K-Ras4A and N-Ras. Earlier data suggested that PDE? extracts K-Ras4B and N-Ras from the PM, but surprisingly not K-Ras4A. Earlier analysis of the crystal structures advanced that the presence of large/charged residues adjacent to the farnesylated site precludes the PDE? interaction. Here, we show that PDE? can bind to farnesylated K-Ras4A and N-Ras like K-Ras4B, albeit not as strongly. This weaker binding, coupled with the stronger anchoring of K-Ras4A in the membrane (but not of electrostatically neutral N-Ras), can explain the observation why PDE? is unable to effectively extract K-Ras4A. We thus propose that farnesylated Ras isoforms can bind PDE? to fulfill the required PM enrichment, and argue that the different environments, PM versus solution, can resolve apparently puzzling Ras observations. These are novel insights that would not be expected based on the crystal structures alone, which provide an elegant rationale for previously puzzling observations of the differential effects of PDE? on farnesylated Ras family proteins.

SUBMITTER: Muratcioglu S

PROVIDER: S-EPMC7891760 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PDEδ Binding to Ras Isoforms Provides a Route to Proper Membrane Localization.

Muratcioglu Serena S Jang Hyunbum H Gursoy Attila A Keskin Ozlem O Nussinov Ruth R

The journal of physical chemistry. B 20170607 24

To signal, Ras isoforms must be enriched at the plasma membrane (PM). It was suggested that phosphodiesterase-δ (PDEδ) can bind and shuttle some farnesylated Ras isoforms to the PM, but not all. Among these, interest focused on K-Ras4B, the most abundant oncogenic Ras isoform. To study PDEδ/Ras interactions, we modeled and simulated the PDEδ/K-Ras4B complex. We obtained structures, which were similar to two subsequently determined crystal structures. We next modeled and simulated complexes of PD ...[more]

PMID: 28540724

Similar Datasets

Project description:BACKGROUND:Ras are small cellular GTPases which regulate diverse cellular processes. It has three isoforms: H-Ras, K-Ras, and N-Ras. Owing to the N-terminus (1-165 residues) sequence homology these isoforms were thought to be functionally redundant. However, only K-Ras-deficient mice but not H-Ras- and N-Ras-deficient mice show embryonic lethality. Similarly, mutations in a given Ras isoform are associated with a particular type of cancer. Moreover, we have previously reported that Ras isoforms perform unique functions in Leishmania major infection. Thus, Ras isoforms are implicated to have signaling and functional specificity but the mechanism remains to be elucidated. RESULT:Using CD40 as a model receptor, we showed that depending on the strength of signaling, specific Ras isoforms are activated. Weak CD40 signal activates N-Ras, whereas strong signal activates H-Ras and K-Ras. Additionally, we showed that suppression of N-Ras expression reduced CD40-induced extracellular signal-regulated kinase-1/2 (ERK-1/2) activation and Interleukin (IL)-10 production; whereas suppression of H-Ras or K-Ras reduced CD40-induced p38 mitogen-activated protein kinase (p38MAPK) activation and IL-12 production. Furthermore, we showed that Ras isoforms have activator (GEF) specificity as weak CD40 signal-activated N-Ras requires Sos-1/2 whereas strong CD40 signal-activated H-Ras/K-Ras requires Ras-GRP as the guanine-nucleotide exchange factor (GEF) inducing ERK-1/2- or p38MAPK-mediated IL-10 or IL-12 productions, respectively, in macrophages. Silencing of syk reduced CD40-induced N-Ras activation but silencing of lyn inhibited H-Ras and K-Ras activation. In CD40 signaling, Ras isoforms also showed effector specificity; while H-Ras and K-Ras showed specificity for phosphatidyl inositol-3 kinase activation at high dose of CD40 stimulation, N-Ras primarily associated with Raf-1 at low dose of CD40 stimulation. Moreover, fractal analysis showed that functional site surface roughness for H-Ras (SurfaceFD?=?2.39) and K-Ras (SurfaceFD?=?2.39) are similar but significantly different from N-Ras (SurfaceFD?=?2.25). CONCLUSION:The activator and effector specificities of Ras isoforms in CD40 signaling indicated their differential involvement in CD40 pathway and in maintaining the reciprocity. Our observations reveal Ras-regulated signaling outcome and its potential for developing Ras isoform-targeted immunotherapy and prophylaxis.

Dataset Information

PDE? Binding to Ras Isoforms Provides a Route to Proper Membrane Localization.

Publications

PDEδ Binding to Ras Isoforms Provides a Route to Proper Membrane Localization.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure