The Plasma Membrane as a Competitive Inhibitor and Positive Allosteric Modulator of KRas4B Signaling.

Abstract:

:Mutant Ras proteins are important drivers of human cancers, yet no approved drugs act directly on this difficult target. Over the last decade, the idea has emerged that oncogenic signaling can be diminished by molecules that drive Ras into orientations in which effector-binding interfaces are occluded by the cell membrane. To support this approach to drug discovery, we characterize the orientational preferences of membrane-bound K-Ras4B in 1.45-ms aggregate time of atomistic molecular dynamics simulations. Individual simulations probe active or inactive states of Ras on membranes with or without anionic lipids. We find that the membrane orientation of Ras is relatively insensitive to its bound guanine nucleotide and activation state but depends strongly on interactions with anionic phosphatidylserine lipids. These lipids slow Ras' translational and orientational diffusion and promote a discrete population in which small changes in orientation control Ras' competence to bind multiple regulator and effector proteins. Our results suggest that compound-directed conversion of constitutively active mutant Ras into functionally inactive forms may be accessible via subtle perturbations of Ras' orientational preferences at the membrane surface.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Neale C,García AE

doi

10.1016/j.bpj.2019.12.039

subject

Has Abstract

pub_date

2020-03-10 00:00:00

pages

1129-1141

issue

5

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(20)30036-9

journal_volume

118

pub_type

杂志文章
  • Examination of the subsarcolemmal tubular system of mammalian skeletal muscle fibers.

    abstract::A subsarcolemmal tubular system network (SSTN) has been detected in skeletal muscle fibers by confocal imaging after the removal of the sarcolemma. Here we confirm the existence and resolve the fine architecture and the localization of the SSTN at an unprecedented level of detail by examining extracellularly applied t...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/j.bpj.2013.04.029

    authors: Jayasinghe ID,Lo HP,Morgan GP,Baddeley D,Parton RG,Soeller C,Launikonis BS

    更新日期:2013-06-04 00:00:00

  • A rabbit ventricular action potential model replicating cardiac dynamics at rapid heart rates.

    abstract::Mathematical modeling of the cardiac action potential has proven to be a powerful tool for illuminating various aspects of cardiac function, including cardiac arrhythmias. However, no currently available detailed action potential model accurately reproduces the dynamics of the cardiac action potential and intracellula...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1529/biophysj.106.98160

    authors: Mahajan A,Shiferaw Y,Sato D,Baher A,Olcese R,Xie LH,Yang MJ,Chen PS,Restrepo JG,Karma A,Garfinkel A,Qu Z,Weiss JN

    更新日期:2008-01-15 00:00:00

  • Protein-Protein Docking Reveals Dynamic Interactions of Tropomyosin on Actin Filaments.

    abstract::Experimental approaches such as fiber diffraction and cryo-electron microscopy reconstruction have defined regulatory positions of tropomyosin on actin but have not, as yet, succeeded at determining key atomic-level contacts between these proteins or fully substantiated the dynamics of their interactions at a structur...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/j.bpj.2020.05.017

    authors: Pavadai E,Lehman W,Rynkiewicz MJ

    更新日期:2020-07-07 00:00:00

  • Physiological differences between the alpha and beta ryanodine receptors of fish skeletal muscle.

    abstract::Two isoforms of the sarcoplasmic reticulum Ca2+ release channel (ryanodine receptor or RYR) are expressed together in the skeletal muscles of most vertebrates. We have studied physiological properties of the two isoforms (alpha and beta) by comparing SR preparations from specialized fish muscles that express the alpha...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/S0006-3495(95)80208-0

    authors: O'Brien J,Valdivia HH,Block BA

    更新日期:1995-02-01 00:00:00

  • Bending elastic modulus of red blood cell membrane derived from buckling instability in micropipet aspiration tests.

    abstract::Observation of cell membrane buckling and cell folding in micropipette aspiration experiments was used to evaluate the bending rigidity of the red blood cell membrane. The suction pressure required to buckle the membrane surface initially was found to be about one-half to two-thirds of the pressure that caused the cel...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/S0006-3495(83)84319-7

    authors: Evans EA

    更新日期:1983-07-01 00:00:00

  • Bilayer conformation of fusion peptide of influenza virus hemagglutinin: a molecular dynamics simulation study.

    abstract::Unraveling the conformation of membrane-bound viral fusion peptides is essential for understanding how those peptides destabilize the bilayer topology of lipids that is important for virus-cell membrane fusion. Here, molecular dynamics (MD) simulations were performed to investigate the conformation of the 20 amino aci...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1529/biophysj.103.024562

    authors: Huang Q,Chen CL,Herrmann A

    更新日期:2004-07-01 00:00:00

  • Imaging nanometer-sized α-synuclein aggregates by superresolution fluorescence localization microscopy.

    abstract::The morphological features of α-synuclein (AS) amyloid aggregation in vitro and in cells were elucidated at the nanoscale by far-field subdiffraction fluorescence localization microscopy. Labeling AS with rhodamine spiroamide probes allowed us to image AS fibrillar structures by fluorescence stochastic nanoscopy with ...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/j.bpj.2012.03.010

    authors: Roberti MJ,Fölling J,Celej MS,Bossi M,Jovin TM,Jares-Erijman EA

    更新日期:2012-04-04 00:00:00

  • Substrate dynamics in enzyme action: rotations of monosaccharide subunits in the binding groove are essential for pectin methylesterase processivity.

    abstract::The dynamical behavior of biomacromolecules is a fundamental property regulating a large number of biological processes. Protein dynamics have been widely shown to play a role in enzyme catalysis; however, the interplay between substrate dynamics and enzymatic activity is less understood. We report insights into the r...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/j.bpj.2013.02.049

    authors: Mercadante D,Melton LD,Jameson GB,Williams MA,De Simone A

    更新日期:2013-04-16 00:00:00

  • Comparison of the biophysical properties of racemic and d-erythro-N-acyl sphingomyelins.

    abstract::In this study stereochemically pure d-erythro-sphingomyelins (SMs) with either 16:0 or 18:1(cisDelta9) as the N-linked acyl-chain were synthesized. Our purpose was to examine the properties of these sphingomyelins and acyl-chain matched racemic (d-erythro/l-threo) sphingomyelins in model membranes. Liquid-expanded d-e...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/S0006-3495(99)76997-3

    authors: Ramstedt B,Slotte JP

    更新日期:1999-09-01 00:00:00

  • Passive tension and stiffness of vertebrate skeletal and insect flight muscles: the contribution of weak cross-bridges and elastic filaments.

    abstract::Tension and dynamic stiffness of passive rabbit psoas, rabbit semitendinosus, and waterbug indirect flight muscles were investigated to study the contribution of weak-binding cross-bridges and elastic filaments (titin and minititin) to the passive mechanical behavior of these muscles. Experimentally, a functional diss...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/S0006-3495(93)81262-1

    authors: Granzier HL,Wang K

    更新日期:1993-11-01 00:00:00

  • Physical determinants of β-barrel membrane protein folding in lipid vesicles.

    abstract::The spontaneous folding of two Neisseria outer membrane proteins, opacity-associated (Opa)(60) and Opa(50) into lipid vesicles was investigated by systematically varying bulk and membrane properties. Centrifugal fractionation coupled with sodium dodecyl sulfate polyacrylamide gel electrophoresis mobility assays enable...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/j.bpj.2011.03.025

    authors: Dewald AH,Hodges JC,Columbus L

    更新日期:2011-05-04 00:00:00

  • Open-Boundary Molecular Dynamics of a DNA Molecule in a Hybrid Explicit/Implicit Salt Solution.

    abstract::The composition and electrolyte concentration of the aqueous bathing environment have important consequences for many biological processes and can profoundly affect the behavior of biomolecules. Nevertheless, because of computational limitations, many molecular simulations of biophysical systems can be performed only ...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/j.bpj.2018.02.042

    authors: Zavadlav J,Sablić J,Podgornik R,Praprotnik M

    更新日期:2018-05-22 00:00:00

  • Sizing membrane pores in lipid vesicles by leakage of co-encapsulated markers: pore formation by melittin.

    abstract::Many toxins and antimicrobial peptides permeabilize membrane vesicles by forming multimeric pores. Determination of the size of such pores is an important first step for understanding their structure and the mechanism of their self-assembly. We report a simple method for sizing pores in vesicles based on the different...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/S0006-3495(97)78822-2

    authors: Ladokhin AS,Selsted ME,White SH

    更新日期:1997-04-01 00:00:00

  • Functional co-assembly among subunits of cyclic-nucleotide-activated, nonselective cation channels, and across species from nematode to human.

    abstract::Cyclic-nucleotide-activated, nonselective cation channels have a central role in sensory transduction. They are most likely tetramers, composed of two subunits (alpha and beta or 1 and 2), with the former, but not the latter, being able to form homomeric cyclic-nucleotide-activated channels. Identified members of this...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/S0006-3495(98)77846-4

    authors: Finn JT,Krautwurst D,Schroeder JE,Chen TY,Reed RR,Yau KW

    更新日期:1998-03-01 00:00:00

  • Thermal unfolding simulations of bacterial flagellin: insight into its refolding before assembly.

    abstract::Flagellin is the subunit of the bacterial filament, the micrometer-long propeller of a bacterial flagellum. The protein is believed to undergo unfolding for transport through the channel of the filament and to refold in a chamber at the end of the channel before being assembled into the growing filament. We report a t...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1529/biophysj.107.123927

    authors: Chng CP,Kitao A

    更新日期:2008-05-15 00:00:00

  • Protein stiffening and entropic stabilization in the subdenaturing limit of guanidine hydrochloride.

    abstract::Subdenaturing concentrations of guanidine hydrochloride (GdnHCl) stabilize proteins. For ferrocytochrome c the stabilization is detected at subglobal level with no measured change in global stability. These deductions are made by comparing observed rates of thermally driven ferrocytochrome cHCO reactions with global u...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1529/biophysj.104.044701

    authors: Kumar R,Prabhu NP,Yadaiah M,Bhuyan AK

    更新日期:2004-10-01 00:00:00

  • Improved resolution of tertiary structure elasticity in muscle protein.

    abstract::Rearrangement of tertiary structure in response to mechanical force (termed tertiary structure elasticity) in the tandem Ig chain is the first mode of elastic response for muscle protein titin. Tertiary structure elasticity occurs at low stretching forces (few tens of pN), and was described at atomic resolution in a r...

    journal_title:Biophysical journal

    pub_type: 信件

    doi:10.1016/j.bpj.2011.01.019

    authors: Hsin J,Schulten K

    更新日期:2011-02-16 00:00:00

  • Protein and virus crystal growth on international microgravity laboratory-2.

    abstract::Two T = 1 and one T = 3 plant viruses, along with a protein, were crystallized in microgravity during the International Microgravity Laboratory-2 (IML-2) mission in July of 1994. The method used was liquid-liquid diffusion in the European Space Agency's Advanced Protein Crystallization Facility (APCF). Distinctive alt...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/S0006-3495(95)79890-3

    authors: Koszelak S,Day J,Leja C,Cudney R,McPherson A

    更新日期:1995-07-01 00:00:00

  • Minor groove deformability of DNA: a molecular dynamics free energy simulation study.

    abstract::The conformational deformability of nucleic acids can influence their function and recognition by proteins. A class of DNA binding proteins including the TATA box binding protein binds to the DNA minor groove, resulting in an opening of the minor groove and DNA bending toward the major groove. Explicit solvent molecul...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1529/biophysj.106.083816

    authors: Zacharias M

    更新日期:2006-08-01 00:00:00

  • Resting myoplasmic free calcium in frog skeletal muscle fibers estimated with fluo-3.

    abstract::Fluo-3 is an unusual tetracarboxylate Ca2+ indicator. For recent lots supplied by Molecular Probes Inc. (Eugene, OR), FMAX, the fluorescence intensity of the indicator in its Ca(2+)-bound form, is approximately 200 times that of FMIN, the fluorescence intensity of the indicator in its Ca(2+)-free form. (For earlier lo...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/S0006-3495(93)81112-3

    authors: Harkins AB,Kurebayashi N,Baylor SM

    更新日期:1993-08-01 00:00:00

  • Structural Thermodynamics of myr-Src(2-19) Binding to Phospholipid Membranes.

    abstract::Many proteins are anchored to lipid bilayer membranes through a combination of hydrophobic and electrostatic interactions. In the case of the membrane-bound nonreceptor tyrosine kinase Src from Rous sarcoma virus, these interactions are mediated by an N-terminal myristoyl chain and an adjacent cluster of six basic ami...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/j.bpj.2015.06.051

    authors: Scheidt HA,Klingler J,Huster D,Keller S

    更新日期:2015-08-04 00:00:00

  • A quantitative approach to analyze binding diffusion kinetics by confocal FRAP.

    abstract::Most of the important types of interactions that occur in cells can be characterized as binding-diffusion type processes, and can be quantified by kinetic rate constants such as diffusion coefficients (D) and binding rate constants (k(on) and k(off)). Confocal FRAP is a potentially important tool for the quantitative ...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/j.bpj.2010.09.013

    authors: Kang M,Day CA,DiBenedetto E,Kenworthy AK

    更新日期:2010-11-03 00:00:00

  • Molecular modeling of nearly full-length ErbB2 receptor.

    abstract::Members of the epidermal growth factor receptor family play important roles in various cellular processes, both in physiological and in pathological conditions. Dimerization and autophosphorylation of these receptor tyrosine kinases are key events of signal transduction. Details of the molecular events of the signalin...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1529/biophysj.104.046003

    authors: Bagossi P,Horváth G,Vereb G,Szöllösi J,Tözsér J

    更新日期:2005-02-01 00:00:00

  • Study of the Expression Transition of Cardiac Myosin Using Polarization-Dependent SHG Microscopy.

    abstract::Detection of the transition between the two myosin isoforms α- and β-myosin in living cardiomyocytes is essential for understanding cardiac physiology and pathology. In this study, the differences in symmetry of polarization spectra obtained from α- and β-myosin in various mammalian ventricles and propylthiouracil-tre...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/j.bpj.2019.12.030

    authors: Yuan C,Zhao X,Wang Z,Borg TK,Ye T,Khalpey ZI,Runyan RB,Shao Y,Gao BZ

    更新日期:2020-03-10 00:00:00

  • The force exerted by a single kinesin molecule against a viscous load.

    abstract::Kinesin is a motor protein that uses the energy derived from the hydrolysis of ATP to power the transport of organelles along microtubules. To probe the mechanism of this chemical-to-mechanical energy transduction reaction, the movement of microtubules across glass surfaces coated with kinesin was perturbed by raising...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/S0006-3495(94)80537-5

    authors: Hunt AJ,Gittes F,Howard J

    更新日期:1994-08-01 00:00:00

  • The properties of chondrocyte membrane reservoirs and their role in impact-induced cell death.

    abstract::Impact loading of articular cartilage causes extensive chondrocyte death. Cell membranes have a limited elastic range of 3-4% strain but are protected from direct stretch during physiological loading by their membrane reservoir, an intricate pattern of membrane folds. Using a finite-element model, we suggested previou...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/j.bpj.2013.08.035

    authors: Moo EK,Amrein M,Epstein M,Duvall M,Abu Osman NA,Pingguan-Murphy B,Herzog W

    更新日期:2013-10-01 00:00:00

  • Model inspired by nuclear pore complex suggests possible roles for nuclear transport receptors in determining its structure.

    abstract::Nuclear transport receptors (NTRs) mediate nucleocytoplasmic transport via their affinity for unstructured proteins (polymers) in the nuclear pore complex (NPC). Here, we have modeled the effect of NTRs on polymeric structure in the nanopore confinement of the NPC central conduit. The model explicitly takes into accou...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/j.bpj.2013.11.013

    authors: Osmanović D,Ford IJ,Hoogenboom BW

    更新日期:2013-12-17 00:00:00

  • Wave propagation through a viscous fluid contained in a tethered, initially stresses, orthotropic elastic tube.

    abstract::To give a realistic representation of the pulse propagation in arteries a theoretical analysis of the wave propagation through a viscous incompressible fluid contained in an initially stressed elastic tube is considered. The tube is assumed to be orthotropic and its longitudinal motion is constrained by a uniformly di...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/s0006-3495(68)86512-9

    authors: Atabek HB

    更新日期:1968-05-01 00:00:00

  • Barrier-free paths of directed protein motion in the erythrocyte plasma membrane.

    abstract::A model is presented for the steric interaction between a plasma membrane protein and the membrane cytoskeleton in the human erythrocyte. The cytoskeleton is treated as a network of polymer chains attached to a flat bilayer, and the membrane protein is a hemisphere of effective radius R(e) with center on the bilayer e...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/S0006-3495(95)79909-X

    authors: Boal DH,Boey SK

    更新日期:1995-08-01 00:00:00

  • Alignment of microscopic particles in electric fields and its biological implications.

    abstract::It is well known that electromagnetic fields cause mechanical forces. If one applies an electrical field to a suspension of microscopic particles, these particles realign themselves along the direction of the field and form pearl-chain-like aggregates. These chains are mostly single stranded but they are frequently mu...

    journal_title:Biophysical journal

    pub_type: 杂志文章

    doi:10.1016/S0006-3495(85)83945-X

    authors: Takashima S,Schwan HP

    更新日期:1985-04-01 00:00:00