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  1. Article ; Online: Molecular recognition of RAS/RAF complex at the membrane

    Timothy Travers / Cesar A. López / Que N. Van / Chris Neale / Marco Tonelli / Andrew G. Stephen / S. Gnanakaran

    Scientific Reports, Vol 8, Iss 1, Pp 1-

    Role of RAF cysteine-rich domain

    2018  Volume 15

    Abstract: Abstract Activation of RAF kinase involves the association of its RAS-binding domain (RBD) and cysteine-rich domain (CRD) with membrane-anchored RAS. However, the overall architecture of the RAS/RBD/CRD ternary complex and the orientations of its ... ...

    Abstract Abstract Activation of RAF kinase involves the association of its RAS-binding domain (RBD) and cysteine-rich domain (CRD) with membrane-anchored RAS. However, the overall architecture of the RAS/RBD/CRD ternary complex and the orientations of its constituent domains at the membrane remain unclear. Here, we have combined all-atom and coarse-grained molecular dynamics (MD) simulations with experimental data to construct and validate a model of membrane-anchored CRD, and used this as a basis to explore models of membrane-anchored RAS/RBD/CRD complex. First, simulations of the CRD revealed that it anchors to the membrane via insertion of its two hydrophobic loops, which is consistent with our NMR measurements of CRD bound to nanodiscs. Simulations of the CRD in the context of membrane-anchored RAS/RBD then show how CRD association with either RAS or RBD could play an unexpected role in guiding the membrane orientations of RAS/RBD. This finding has implications for the formation of RAS-RAS dimers, as different membrane orientations of RAS expose distinct putative dimerization interfaces.
    Keywords Medicine ; R ; Science ; Q
    Subject code 612
    Language English
    Publishing date 2018-05-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation

    Timothy H. Tran / Albert H. Chan / Lucy C. Young / Lakshman Bindu / Chris Neale / Simon Messing / Srisathiyanarayanan Dharmaiah / Troy Taylor / John-Paul Denson / Dominic Esposito / Dwight V. Nissley / Andrew G. Stephen / Frank McCormick / Dhirendra K. Simanshu

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 16

    Abstract: The molecular details of the RAS-RAF interaction are still not fully understood. Here, the authors present crystal structures of wild-type and mutant KRAS in complex with the RAS-binding and membrane-interacting cysteine-rich domains of RAF1, and propose ...

    Abstract The molecular details of the RAS-RAF interaction are still not fully understood. Here, the authors present crystal structures of wild-type and mutant KRAS in complex with the RAS-binding and membrane-interacting cysteine-rich domains of RAF1, and propose a model of the membrane-bound RAS-RAF complex.
    Keywords Science ; Q
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Structures of N-terminally processed KRAS provide insight into the role of N-acetylation

    Srisathiyanarayanan Dharmaiah / Timothy H. Tran / Simon Messing / Constance Agamasu / William K. Gillette / Wupeng Yan / Timothy Waybright / Patrick Alexander / Dominic Esposito / Dwight V. Nissley / Frank McCormick / Andrew G. Stephen / Dhirendra K. Simanshu

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 15

    Abstract: Abstract Although post-translational modification of the C-terminus of RAS has been studied extensively, little is known about N-terminal processing. Mass spectrometric characterization of KRAS expressed in mammalian cells showed cleavage of the ... ...

    Abstract Abstract Although post-translational modification of the C-terminus of RAS has been studied extensively, little is known about N-terminal processing. Mass spectrometric characterization of KRAS expressed in mammalian cells showed cleavage of the initiator methionine (iMet) and N-acetylation of the nascent N-terminus. Interestingly, structural studies on GDP- and GMPPNP-bound KRAS lacking the iMet and N-acetylation resulted in Mg2+-free structures of KRAS with flexible N-termini. In the Mg2+-free KRAS-GDP structure, the flexible N-terminus causes conformational changes in the interswitch region resulting in a fully open conformation of switch I. In the Mg2+-free KRAS-GMPPNP structure, the flexible N-terminus causes conformational changes around residue A59 resulting in the loss of Mg2+ and switch I in the inactive state 1 conformation. Structural studies on N-acetylated KRAS-GDP lacking the iMet revealed the presence of Mg2+ and a conformation of switch regions also observed in the structure of GDP-bound unprocessed KRAS with the iMet. In the absence of the iMet, the N-acetyl group interacts with the central beta-sheet and stabilizes the N-terminus and the switch regions. These results suggest there is crosstalk between the N-terminus and the Mg2+ binding site, and that N-acetylation plays an important role by stabilizing the N-terminus of RAS upon excision of the iMet.
    Keywords Medicine ; R ; Science ; Q
    Subject code 540
    Language English
    Publishing date 2019-07-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: PDE6D Inhibitors with a New Design Principle Selectively Block K‑Ras Activity

    Farid A. Siddiqui / Catharina Alam / Petja Rosenqvist / Mikko Ora / Ahmed Sabt / Ganesh babu Manoharan / Lakshman Bindu / Sunday Okutachi / Marie Catillon / Troy Taylor / Omaima M. Abdelhafez / Harri Lönnberg / Andrew G. Stephen / Anastassios C. Papageorgiou / Pasi Virta / Daniel Abankwa

    ACS Omega, Vol 5, Iss 1, Pp 832-

    2019  Volume 842

    Keywords Chemistry ; QD1-999
    Language English
    Publishing date 2019-12-01T00:00:00Z
    Publisher American Chemical Society
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article: Inhibition of Ras/Raf/MEK/ERK Pathway Signaling by a Stress-Induced Phospho-Regulatory Circuit

    Ritt, Daniel A / Andrew G. Stephen / David E. Durrant / Deborah K. Morrison / Lakshman Bindu / María T. Abreu-Blanco / Matthew Holderfield / Ming Zhou / Suzanne I. Specht

    Molecular cell. 2016 Dec. 01, v. 64, no. 5

    2016  

    Abstract: Ras pathway signaling plays a critical role in cell growth control and is often upregulated in human cancer. The Raf kinases selectively interact with GTP-bound Ras and are important effectors of Ras signaling, functioning as the initiating kinases in ... ...

    Abstract Ras pathway signaling plays a critical role in cell growth control and is often upregulated in human cancer. The Raf kinases selectively interact with GTP-bound Ras and are important effectors of Ras signaling, functioning as the initiating kinases in the ERK cascade. Here, we identify a route for the phospho-inhibition of Ras/Raf/MEK/ERK pathway signaling that is mediated by the stress-activated JNK cascade. We find that key Ras pathway components, the RasGEF Sos1 and the Rafs, are phosphorylated on multiple S/TP sites in response to JNK activation and that the hyperphosphorylation of these sites renders the Rafs and Sos1 unresponsive to upstream signals. This phospho-regulatory circuit is engaged by cancer therapeutics, such as rigosertib and paclitaxel/Taxol, that activate JNK through mitotic and oxidative stress as well as by physiological regulators of the JNK cascade and may function as a signaling checkpoint to suppress the Ras pathway during conditions of cellular stress.
    Keywords cell growth ; humans ; mitogen-activated protein kinase ; mitosis ; neoplasms ; oxidative stress ; paclitaxel ; signal transduction ; therapeutics
    Language English
    Dates of publication 2016-1201
    Size p. 875-887.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2016.10.029
    Database NAL-Catalogue (AGRICOLA)

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