biostudies-literatureVan QNNCRR NIH HHSDOE | NNSA | Los Alamos National LaboratoryHHS | National Institutes of HealthCCR NIH HHSU.S. Department of EnergyDOE | LDRD | Oak Ridge National LaboratoryDOE | LDRD | Argonne National LaboratoryHHS | NIH | National Cancer InstituteDOE | LDRD | Lawrence Livermore National LaboratoryNCI NIH HHSU.S. Department of CommerceNIGMS NIH HHSNational Science Foundation24258-24268https://www.ebi.ac.uk/biostudies/studies/S-EPMC7533834biostudies-literatureUnknown117(39)The small GTPase KRAS is localized at the plasma membrane where it functions as a molecular switch, coupling extracellular growth factor stimulation to intracellular signaling networks. In this process, KRAS recruits effectors, such as RAF kinase, to the plasma membrane where they are activated by a series of complex molecular steps. Defining the membrane-bound state of KRAS is fundamental to understanding the activation of RAF kinase and in evaluating novel therapeutic opportunities for the inhibition of oncogenic KRAS-mediated signaling. We combined multiple biophysical measurements and computational methodologies to generate a consensus model for authentically processed, membrane-anchored KRAS. In contrast to the two membrane-proximal conformations previously reported, we identify a thiProceedings of the National Academy of Sciences of the United States of AmericaUncovering a membrane-distal conformation of KRAS available to recruit RAF to the plasma membrane.PMC7533834S10 RR028438P50 GM085273DE-AC52-07NA27344JDACS4CDE-AC05-00OR22725S10 RR029220S10RR023438HHSN261200800001ES10RR08438S10 RR025062DMB-8415048HHSN261200800001CP50GM085273S10 RR002781P41 GM103399P41GM103399S10RR025062S10 RR023438S10RR029220OIA-9977486DE-AC02-06-CH11357S10RR02781S10 RR008438P41 GM103422DE-AC5206NA25396BIR-921439470NANB17H299P41GM103422Ramanathan AScott DTonelli MTaylor TAlexander PYe XLopez CAChertov OVan QNBhowmik DGillette WKLosche MNissley DVStephen AGEsposito DSimanshu DKNiu BMcCormick FGnanakaran SHeinrich FMessing SStanley CBDrew MWestler WMTran THGross MLMarkley JLFrank PHHengartner NWfalseUncovering a membrane-distal conformation of KRAS available to recruit RAF to the plasma membrane.The small GTPase KRAS is localized at the plasma membrane where it functions as a molecular switch, coupling extracellular growth factor stimulation to intracellular signaling networks. In this process, KRAS recruits effectors, such as RAF kinase, to the plasma membrane where they are activated by a series of complex molecular steps. Defining the membrane-bound state of KRAS is fundamental to understanding the activation of RAF kinase and in evaluating novel therapeutic opportunities for the inhibition of oncogenic KRAS-mediated signaling. We combined multiple biophysical measurements and computational methodologies to generate a consensus model for authentically processed, membrane-anchored KRAS. In contrast to the two membrane-proximal conformations previously reported, we identify a thi2020-01-01T00:00:00Z2020 Sep2026-04-29T06:26:07.526Z2021-03-12T08:19:05ZS-EPMC75338343291305610.1073/pnas.2006504117