SwePub
Sök i LIBRIS databas

  Utökad sökning

onr:"swepub:oai:DiVA.org:kth-252604"
 

Sökning: onr:"swepub:oai:DiVA.org:kth-252604" > Oncogenic mutations...

Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope

Orellana, Laura (författare)
Stockholms universitet,KTH,Science for Life Laboratory, SciLifeLab,Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab)
Thorne, Amy H. (författare)
Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA.
Lema, Rafael (författare)
Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Barcelona 08028, Catalonia, Spain.
visa fler...
Gustavsson, Johan (författare)
KTH,Beräkningsvetenskap och beräkningsteknik (CST)
Parisian, Alison D. (författare)
Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA.
Hospital, Adam (författare)
Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Barcelona 08028, Catalonia, Spain.
Cordeiro, Tiago N. (författare)
Univ Nova Lisboa, Inst Tecnol Quim & Biol Antonio Xavier, P-2780157 Oeiras, Portugal.
Bernado, Pau (författare)
Univ Montpellier, CNRS, INSERM, CBS, F-34090 Montpellier, France.
Scott, Andrew M. (författare)
Austin Hosp, Olivia Newton John Canc Res Inst, Heidelberg, Vic 3084, Australia.;La Trobe Univ, Sch Canc Med, Bundoora, Vic 3086, Australia.
Brun-Heath, Isabelle (författare)
Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Barcelona 08028, Catalonia, Spain.
Lindahl, Erik, 1972- (författare)
Stockholms universitet,KTH,Science for Life Laboratory, SciLifeLab,Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab)
Cavenee, Webster K. (författare)
Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA.
Furnari, Frank B. (författare)
Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA.
Orozco, Modesto (författare)
Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Barcelona 08028, Catalonia, Spain.;Univ Barcelona, Dept Biochem & Biomed, E-08028 Barcelona, Catalonia, Spain.
visa färre...
 (creator_code:org_t)
NATL ACAD SCIENCES, 2019
2019
Engelska.
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 116:20, s. 10009-10018
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • Epidermal growth factor receptor (EGFR) signaling is initiated by a large ligand-favored conformational change of the extracellular domain (ECD) from a closed, self-inhibited tethered monomer, to an open untethered state, which exposes a loop required for strong dimerization and activation. In glioblastomas (GBMs), structurally heterogeneous missense and deletion mutations concentrate at the ECD for unclear reasons. We explore the conformational impact of GBM missense mutations, combining elastic network models (ENMs) with multiple molecular dynamics (MD) trajectories. Our simulations reveal that the main missense class, located at the I-II interface away from the self-inhibitory tether, can unexpectedly favor spontaneous untethering to a compact intermediate state, here validated by small-angle X-ray scattering (SAXS). Significantly, such intermediate is characterized by the rotation of a large ECD fragment (N-TR1), deleted in the most common GBM mutation, EGFRvIII, and that makes accessible a cryptic epitope characteristic of cancer cells. This observation suggested potential structural equivalence of missense and deletion ECD changes in GBMs. Corroborating this hypothesis, our FACS, in vitro, and in vivo data demonstrate that entirely different ECD variants all converge to remove N-TR1 steric hindrance from the 806-epitope, which we show is allosterically coupled to an intermediate kinase and hallmarks increased oncogenicity. Finally, the detected extraintracellular coupling allows for synergistic cotargeting of the intermediate with mAb806 and inhibitors, which is proved herein.

Ämnesord

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences (hsv//eng)
NATURVETENSKAP  -- Biologiska vetenskaper (hsv//swe)

Nyckelord

cancer
mutational heterogeneity
structural convergence
intermediate
cryptoepitope

Publikations- och innehållstyp

ref (ämneskategori)
art (ämneskategori)
 
pil uppåt Stäng

Kopiera och spara länken för att återkomma till aktuell vy