Positive Feedback in Ras Activation by Full-length SOS Arises from Autoinhibition Release Mechanism

Overview

Journal Biophys J

Publisher Cell Press

Specialty Biophysics

Date 2024 Jul 18

PMID 39021073

Authors

He Ren

Albert A Lee

L J Nugent Lew

Joseph B DeGrandchamp

Jay T Groves

Affiliations

Soon will be listed here.

Abstract

Signaling through the Ras-MAPK pathway can exhibit switch-like activation, which has been attributed to the underlying positive feedback and bimodality in the activation of RasGDP to RasGTP by SOS. SOS contains both catalytic and allosteric Ras binding sites, and a common assumption is that allosteric activation selectively by RasGTP provides the mechanism of positive feedback. However, recent single-molecule studies have revealed that SOS catalytic rates are independent of the nucleotide state of Ras in the allosteric binding site, raising doubt about this as a positive feedback mechanism. Here, we perform detailed kinetic analyses of receptor-mediated recruitment of full-length SOS to the membrane while simultaneously monitoring its catalytic activation of Ras. These results, along with kinetic modeling, expose the autoinhibition release step in SOS, rather than either recruitment or allosteric activation, as the underlying mechanism giving rise to positive feedback in Ras activation.

Citing Articles

Bridging molecular to cellular scales for models of membrane receptor signaling.

Peterson K, Slepchenko B, Loew L bioRxiv. 2024; .

PMID: 39677765 PMC: 11643039. DOI: 10.1101/2024.12.04.626844.

Ras signaling mechanisms: New insights from single-molecule biophysics.

McCombs A, Armendariz J, Falke J Biophys J. 2024; 123(19):3277-3280.

PMID: 39217418 PMC: 11480753. DOI: 10.1016/j.bpj.2024.08.025.

References

Huang W, Yan Q, Lin W, Chung J, Hansen S, Christensen S . Phosphotyrosine-mediated LAT assembly on membranes drives kinetic bifurcation in recruitment dynamics of the Ras activator SOS. Proc Natl Acad Sci U S A. 2016; 113(29):8218-23. PMC: 4961118. DOI: 10.1073/pnas.1602602113. View

Chardin P, Camonis J, Gale N, Van Aelst L, Schlessinger J, Wigler M . Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science. 1993; 260(5112):1338-43. DOI: 10.1126/science.8493579. View

McAffee D, ODair M, Lin J, Low-Nam S, Wilhelm K, Kim S . Discrete LAT condensates encode antigen information from single pMHC:TCR binding events. Nat Commun. 2022; 13(1):7446. PMC: 9718779. DOI: 10.1038/s41467-022-35093-9. View

Kubiseski T, Chook Y, Parris W, Rozakis-Adcock M, Pawson T . High affinity binding of the pleckstrin homology domain of mSos1 to phosphatidylinositol (4,5)-bisphosphate. J Biol Chem. 1997; 272(3):1799-804. DOI: 10.1074/jbc.272.3.1799. View

Lee A, Kim N, Alvarez S, Ren H, DeGrandchamp J, Lew L . Bimodality in Ras signaling originates from processivity of the Ras activator SOS without deterministic bistability. Sci Adv. 2024; 10(25):eadi0707. PMC: 11192083. DOI: 10.1126/sciadv.adi0707. View

Bourne H, Sanders D, McCormick F . The GTPase superfamily: a conserved switch for diverse cell functions. Nature. 1990; 348(6297):125-32. DOI: 10.1038/348125a0. View

Vo U, Vajpai N, Flavell L, Bobby R, Breeze A, Embrey K . Monitoring Ras Interactions with the Nucleotide Exchange Factor Son of Sevenless (Sos) Using Site-specific NMR Reporter Signals and Intrinsic Fluorescence. J Biol Chem. 2015; 291(4):1703-1718. PMC: 4722452. DOI: 10.1074/jbc.M115.691238. View

Lowenstein E, Daly R, Batzer A, Li W, Margolis B, Lammers R . The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992; 70(3):431-42. DOI: 10.1016/0092-8674(92)90167-b. View

Lee Y, Low-Nam S, Chung J, Hansen S, Lam H, Alvarez S . Mechanism of SOS PR-domain autoinhibition revealed by single-molecule assays on native protein from lysate. Nat Commun. 2017; 8:15061. PMC: 5414354. DOI: 10.1038/ncomms15061. View

10.

Jun J, Rubio I, Roose J . Regulation of ras exchange factors and cellular localization of ras activation by lipid messengers in T cells. Front Immunol. 2013; 4:239. PMC: 3762125. DOI: 10.3389/fimmu.2013.00239. View

11.

Lee A, Huang W, Hansen S, Kim N, Alvarez S, Groves J . Stochasticity and positive feedback enable enzyme kinetics at the membrane to sense reaction size. Proc Natl Acad Sci U S A. 2021; 118(47). PMC: 8617498. DOI: 10.1073/pnas.2103626118. View

12.

Sondermann H, Soisson S, Boykevisch S, Yang S, Bar-Sagi D, Kuriyan J . Structural analysis of autoinhibition in the Ras activator Son of sevenless. Cell. 2004; 119(3):393-405. DOI: 10.1016/j.cell.2004.10.005. View

13.

Christensen S, Tu H, Jun J, Alvarez S, Triplet M, Iwig J . One-way membrane trafficking of SOS in receptor-triggered Ras activation. Nat Struct Mol Biol. 2016; 23(9):838-46. PMC: 5016256. DOI: 10.1038/nsmb.3275. View

14.

Gureasko J, Galush W, Boykevisch S, Sondermann H, Bar-Sagi D, Groves J . Membrane-dependent signal integration by the Ras activator Son of sevenless. Nat Struct Mol Biol. 2008; 15(5):452-61. PMC: 2440660. DOI: 10.1038/nsmb.1418. View

15.

Huang W, Alvarez S, Kondo Y, Lee Y, Chung J, Lam H . A molecular assembly phase transition and kinetic proofreading modulate Ras activation by SOS. Science. 2019; 363(6431):1098-1103. PMC: 6563836. DOI: 10.1126/science.aau5721. View

16.

Hillig R, Sautier B, Schroeder J, Moosmayer D, Hilpmann A, Stegmann C . Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc Natl Acad Sci U S A. 2019; 116(7):2551-2560. PMC: 6377443. DOI: 10.1073/pnas.1812963116. View

17.

Das J, Ho M, Zikherman J, Govern C, Yang M, Weiss A . Digital signaling and hysteresis characterize ras activation in lymphoid cells. Cell. 2009; 136(2):337-51. PMC: 2662698. DOI: 10.1016/j.cell.2008.11.051. View

18.

Lin C, Nocka L, Stinger B, DeGrandchamp J, Lew L, Alvarez S . A two-component protein condensate of the EGFR cytoplasmic tail and Grb2 regulates Ras activation by SOS at the membrane. Proc Natl Acad Sci U S A. 2022; 119(19):e2122531119. PMC: 9181613. DOI: 10.1073/pnas.2122531119. View

19.

Bandaru P, Kondo Y, Kuriyan J . The Interdependent Activation of Son-of-Sevenless and Ras. Cold Spring Harb Perspect Med. 2018; 9(2). PMC: 6360870. DOI: 10.1101/cshperspect.a031534. View

20.

Hoang H, Umutesi H, Heo J . Allosteric autoactivation of SOS and its kinetic mechanism. Small GTPases. 2019; 12(1):44-59. PMC: 7781538. DOI: 10.1080/21541248.2019.1601954. View