Presence or Absence of Ras Dimerization Shows Distinct Kinetic Signature in Ras-Raf Interaction

Sarkar, Sumantra; García, Angel E.

doi:10.1016/j.bpj.2020.03.004

Title: Presence or Absence of Ras Dimerization Shows Distinct Kinetic Signature in Ras-Raf Interaction

Abstract

Initiations of cell signaling pathways often occur through the formation of multiprotein complexes that form through protein-protein interactions. Therefore, detecting their presence is central to understanding the function of a cell signaling pathway, aberration of which often leads to fatal diseases, including cancers. However, the multiprotein complexes are often difficult to detect using microscopes due to their small sizes. Therefore, currently, their presence can be only detected through indirect means. In this article, we propose to investigate the presence or absence of protein complexes through some easily measurable kinetic parameters, such as activation rates. As a proof of concept, we investigate the Ras-Raf system, a well-characterized cell signaling system. It has been hypothesized that Ras dimerization is necessary to create activated Raf dimers. Although there are circumstantial evidences supporting the Ras dimerization hypothesis, direct proof of Ras dimerization is still inconclusive. In the absence of conclusive direct experimental proof, this hypothesis can only be examined through indirect evidences of Ras dimerization. In this article, using a multiscale simulation technique, we provide multiple criteria that distinguishes an activation mechanism involving Ras dimerization from another mechanism that does not involve Ras dimerization. Here, the provided criteria will be useful in the investigationmore »« less

Authors:: Sarkar, Sumantra; García, Angel E.

Publication Date:: Wed Apr 01 00:00:00 EDT 2020

Research Org.:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Org.:: USDOE National Nuclear Security Administration (NNSA); USDOE Laboratory Directed Research and Development (LDRD) Program

OSTI Identifier:: 1779530

Alternate Identifier(s):: OSTI ID: 1606347; OSTI ID: 1615541

Report Number(s):: LA-UR-19-24762
Journal ID: ISSN 0006-3495; S0006349520302344; PII: S0006349520302344

Grant/Contract Number:: AC52-06NA25396; 89233218CNA000001

Resource Type:: Published Article

Journal Name:: Biophysical Journal

Additional Journal Information:: Journal Name: Biophysical Journal Journal Volume: 118 Journal Issue: 8; Journal ID: ISSN 0006-3495

Publisher:: Elsevier

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES

Citation Formats


                    Sarkar, Sumantra, and García, Angel E. Presence or Absence of Ras Dimerization Shows Distinct Kinetic Signature in Ras-Raf Interaction.  United States: N. p., 2020. 
Web.  doi:10.1016/j.bpj.2020.03.004.

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                    Sarkar, Sumantra, & García, Angel E. Presence or Absence of Ras Dimerization Shows Distinct Kinetic Signature in Ras-Raf Interaction.  United States.  https://doi.org/10.1016/j.bpj.2020.03.004

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                    Sarkar, Sumantra, and García, Angel E. Wed .  
"Presence or Absence of Ras Dimerization Shows Distinct Kinetic Signature in Ras-Raf Interaction".  United States.  https://doi.org/10.1016/j.bpj.2020.03.004.

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@article{osti_1779530,

  title        = {Presence or Absence of Ras Dimerization Shows Distinct Kinetic Signature in Ras-Raf Interaction},

  author       = {Sarkar, Sumantra and García, Angel E.},

  abstractNote = {Initiations of cell signaling pathways often occur through the formation of multiprotein complexes that form through protein-protein interactions. Therefore, detecting their presence is central to understanding the function of a cell signaling pathway, aberration of which often leads to fatal diseases, including cancers. However, the multiprotein complexes are often difficult to detect using microscopes due to their small sizes. Therefore, currently, their presence can be only detected through indirect means. In this article, we propose to investigate the presence or absence of protein complexes through some easily measurable kinetic parameters, such as activation rates. As a proof of concept, we investigate the Ras-Raf system, a well-characterized cell signaling system. It has been hypothesized that Ras dimerization is necessary to create activated Raf dimers. Although there are circumstantial evidences supporting the Ras dimerization hypothesis, direct proof of Ras dimerization is still inconclusive. In the absence of conclusive direct experimental proof, this hypothesis can only be examined through indirect evidences of Ras dimerization. In this article, using a multiscale simulation technique, we provide multiple criteria that distinguishes an activation mechanism involving Ras dimerization from another mechanism that does not involve Ras dimerization. Here, the provided criteria will be useful in the investigation of not only Ras-Raf interaction but also other two-protein interactions.},

  doi          = {10.1016/j.bpj.2020.03.004},

  journal      = {Biophysical Journal},

  number       = 8,

  volume       = 118,

  place        = {United States},

  year         = {Wed Apr 01 00:00:00 EDT 2020},

  month        = {Wed Apr 01 00:00:00 EDT 2020}

}

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Title: Presence or Absence of Ras Dimerization Shows Distinct Kinetic Signature in Ras-Raf Interaction

Abstract

Citation Formats

Computational Approaches for Analyzing Information Flow in Biological Networks journal, April 2012

Raf Kinase Inhibitory Protein Regulates Raf-1 but Not B-Raf Kinase Activation journal, July 2005

Oligomeric structure of p21 ras proteins as determined by radiation inactivation. journal, July 1988

A molecular rotor for measuring viscosity in plasma membranes of live cells journal, January 2014

Dimerization in MAP-kinase signaling journal, January 2000

Combining molecular dynamics with mesoscopic Green’s function reaction dynamics simulations journal, December 2015

Dimerization in GPCR mobility and signaling journal, February 2010

Membrane-associated Ras dimers are isoform-specific: K-Ras dimers differ from H-Ras dimers journal, June 2016

Multiscale simulations of anisotropic particles combining molecular dynamics and Green’s function reaction dynamics journal, March 2017

Role of Repulsive Forces in Determining the Equilibrium Structure of Simple Liquids journal, June 1971

Measuring the Viscosity of the Escherichia coli Plasma Membrane Using Molecular Rotors journal, October 2016

Ras nanoclusters: Versatile lipid-based signaling platforms journal, April 2015

Ras and the Plasma Membrane: A Complicated Relationship journal, December 2017

Computational and biochemical characterization of two partially overlapping interfaces and multiple weak-affinity K-Ras dimers journal, January 2017

Ras oncogenes: split personalities journal, July 2008

Raf Family Kinases: Old Dogs Have Learned New Tricks journal, March 2011

Radicicol Leads to Selective Depletion of Raf Kinase and Disrupts K-Ras-activated Aberrant Signaling Pathway journal, January 1998

RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF journal, February 2010

The Ras G Domain Lacks the Intrinsic Propensity to Form Dimers journal, September 2015

Single Molecule Diffusion of Membrane-Bound Proteins: Window into Lipid Contacts and Bilayer Dynamics journal, November 2010

KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS journal, February 2018

N-Ras Forms Dimers at POPC Membranes journal, October 2012

Network Analysis of Oncogenic Ras Activation in Cancer journal, October 2007

Kinetic laws, phase-phase expansions, renormalization group, and INR calibration journal, April 2009

RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E) journal, November 2011

Spatio-temporal correlations can drastically change the response of a MAPK pathway journal, January 2010

Ras-GTP dimers activate the Mitogen-Activated Protein Kinase (MAPK) pathway journal, June 2015

eGFRD in all dimensions journal, February 2019

Regulation of RAF protein kinases in ERK signalling journal, April 2015

Effects of Raf Dimerization and Its Inhibition on Normal and Disease-Associated Raf Signaling journal, February 2013

Regulation and Role of Raf-1/B-Raf Heterodimerization journal, March 2006

A dimerization-dependent mechanism drives RAF catalytic activation journal, September 2009

The mystery of membrane organization: composition, regulation and roles of lipid rafts journal, March 2017

Physics of chemoreception journal, November 1977

C HEMOKINE S IGNALING AND F UNCTIONAL R ESPONSES : The Role of Receptor Dimerization and TK Pathway Activation journal, April 2001

RAS oncogenes: the first 30 years journal, June 2003

RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth journal, February 2010

Formation of the Ras Dimer Is Essential for Raf-1 Activation journal, February 2000

Ras in Cancer and Developmental Diseases journal, March 2011

The power of two: protein dimerization in biology journal, November 2004

RAS Interaction with PI3K: More Than Just Another Effector Pathway journal, March 2011

Oncogenic K-Ras Binds to an Anionic Membrane in Two Distinct Orientations: A Molecular Dynamics Analysis journal, March 2016

Green’s-function reaction dynamics: A particle-based approach for simulating biochemical networks in time and space journal, December 2005

B-RAF is a therapeutic target in melanoma journal, June 2004

Protease-activated receptor-3 (PAR3) regulates PAR1 signaling by receptor dimerization journal, March 2007

Dimerization of cell surface receptors in signal transduction journal, January 1995

Cell regulation: determined to signal discrete cooperation journal, October 2009

Covalent Ras Dimerization on Membrane Surfaces through Photosensitized Oxidation journal, February 2016

Spatio-temporal segregation of Ras signals: one ship, three anchors, many harbors journal, August 2006

K-Ras4B Remains Monomeric on Membranes over a Wide Range of Surface Densities and Lipid Compositions journal, January 2018

Self organization of membrane proteins via dimerization journal, May 2003

Ras oncogenes and their downstream targets journal, August 2007

Signalling ballet in space and time journal, June 2010

RAS Proteins and Their Regulators in Human Disease journal, June 2017

Ras history: The saga continues journal, July 2010

Drugging RAS: Know the enemy journal, March 2017

GTP-Dependent K-Ras Dimerization journal, July 2015

An efficient multi-scale Green’s function reaction dynamics scheme journal, November 2017

MAD contortions: conformational dimerization boosts spindle checkpoint signaling journal, December 2007

Molecular recognition of RAS/RAF complex at the membrane: Role of RAF cysteine-rich domain journal, May 2018

Simulating Biochemical Networks at the Particle Level and in Time and Space: Green’s Function Reaction Dynamics journal, April 2005

Computational Approaches for Analyzing Information Flow in Biological Networks
journal, April 2012

Raf Kinase Inhibitory Protein Regulates Raf-1 but Not B-Raf Kinase Activation
journal, July 2005

Oligomeric structure of p21 ras proteins as determined by radiation inactivation.
journal, July 1988

A molecular rotor for measuring viscosity in plasma membranes of live cells
journal, January 2014

Dimerization in MAP-kinase signaling
journal, January 2000

Combining molecular dynamics with mesoscopic Green’s function reaction dynamics simulations
journal, December 2015

Dimerization in GPCR mobility and signaling
journal, February 2010

Membrane-associated Ras dimers are isoform-specific: K-Ras dimers differ from H-Ras dimers
journal, June 2016

Multiscale simulations of anisotropic particles combining molecular dynamics and Green’s function reaction dynamics
journal, March 2017

Role of Repulsive Forces in Determining the Equilibrium Structure of Simple Liquids
journal, June 1971

Measuring the Viscosity of the Escherichia coli Plasma Membrane Using Molecular Rotors
journal, October 2016

Ras nanoclusters: Versatile lipid-based signaling platforms
journal, April 2015

Ras and the Plasma Membrane: A Complicated Relationship
journal, December 2017

Computational and biochemical characterization of two partially overlapping interfaces and multiple weak-affinity K-Ras dimers
journal, January 2017

Ras oncogenes: split personalities
journal, July 2008

Raf Family Kinases: Old Dogs Have Learned New Tricks
journal, March 2011

Radicicol Leads to Selective Depletion of Raf Kinase and Disrupts K-Ras-activated Aberrant Signaling Pathway
journal, January 1998

RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF
journal, February 2010

The Ras G Domain Lacks the Intrinsic Propensity to Form Dimers
journal, September 2015

Single Molecule Diffusion of Membrane-Bound Proteins: Window into Lipid Contacts and Bilayer Dynamics
journal, November 2010

KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS
journal, February 2018

N-Ras Forms Dimers at POPC Membranes
journal, October 2012

Network Analysis of Oncogenic Ras Activation in Cancer
journal, October 2007

Kinetic laws, phase-phase expansions, renormalization group, and INR calibration
journal, April 2009

RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)
journal, November 2011

Spatio-temporal correlations can drastically change the response of a MAPK pathway
journal, January 2010

Ras-GTP dimers activate the Mitogen-Activated Protein Kinase (MAPK) pathway
journal, June 2015

eGFRD in all dimensions
journal, February 2019

Regulation of RAF protein kinases in ERK signalling
journal, April 2015

Effects of Raf Dimerization and Its Inhibition on Normal and Disease-Associated Raf Signaling
journal, February 2013

Regulation and Role of Raf-1/B-Raf Heterodimerization
journal, March 2006

A dimerization-dependent mechanism drives RAF catalytic activation
journal, September 2009

The mystery of membrane organization: composition, regulation and roles of lipid rafts
journal, March 2017

Physics of chemoreception
journal, November 1977

C HEMOKINE S IGNALING AND F UNCTIONAL R ESPONSES : The Role of Receptor Dimerization and TK Pathway Activation
journal, April 2001

RAS oncogenes: the first 30 years
journal, June 2003

RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth
journal, February 2010

Formation of the Ras Dimer Is Essential for Raf-1 Activation
journal, February 2000

Ras in Cancer and Developmental Diseases
journal, March 2011

The power of two: protein dimerization in biology
journal, November 2004

RAS Interaction with PI3K: More Than Just Another Effector Pathway
journal, March 2011

Oncogenic K-Ras Binds to an Anionic Membrane in Two Distinct Orientations: A Molecular Dynamics Analysis
journal, March 2016

Green’s-function reaction dynamics: A particle-based approach for simulating biochemical networks in time and space
journal, December 2005

B-RAF is a therapeutic target in melanoma
journal, June 2004

Protease-activated receptor-3 (PAR3) regulates PAR1 signaling by receptor dimerization
journal, March 2007

Dimerization of cell surface receptors in signal transduction
journal, January 1995

Cell regulation: determined to signal discrete cooperation
journal, October 2009

Covalent Ras Dimerization on Membrane Surfaces through Photosensitized Oxidation
journal, February 2016

Spatio-temporal segregation of Ras signals: one ship, three anchors, many harbors
journal, August 2006

K-Ras4B Remains Monomeric on Membranes over a Wide Range of Surface Densities and Lipid Compositions
journal, January 2018

Self organization of membrane proteins via dimerization
journal, May 2003

Ras oncogenes and their downstream targets
journal, August 2007

Signalling ballet in space and time
journal, June 2010

RAS Proteins and Their Regulators in Human Disease
journal, June 2017

Ras history: The saga continues
journal, July 2010

Drugging RAS: Know the enemy
journal, March 2017

GTP-Dependent K-Ras Dimerization
journal, July 2015

An efficient multi-scale Green’s function reaction dynamics scheme
journal, November 2017

MAD contortions: conformational dimerization boosts spindle checkpoint signaling
journal, December 2007

Molecular recognition of RAS/RAF complex at the membrane: Role of RAF cysteine-rich domain
journal, May 2018

Simulating Biochemical Networks at the Particle Level and in Time and Space: Green’s Function Reaction Dynamics
journal, April 2005