Uncovering a membrane-distal conformation of KRAS available to recruit RAF to the plasma membrane | Zendy

Que N. Van | Zendy; César A. López | Zendy; Marco Tonelli | Zendy; Troy Taylor | Zendy; Ben Niu | Zendy; Christopher B. Stanley | Zendy; Debsindhu Bhowmik | Zendy; Timothy H. Tran | Zendy; Peter Frank | Zendy; Simon Messing | Zendy; Patrick Alexander | Zendy; Daniel R. Scott | Zendy; Xiaoying Ye | Zendy; Matt Drew | Zendy; Oleg Chertov | Zendy; Mathias Lösche | Zendy; Arvind Ramanathan | Zendy; Michael L. Gross | Zendy; Nicolas Hengartner | Zendy; William M. Westler | Zendy; John L. Markley | Zendy; Dhirendra K. Simanshu | Zendy; Dwight V. Nissley | Zendy; William Gillette | Zendy; Dominic Esposito | Zendy; Frank McCormick | Zendy; S. Gnanakaran | Zendy; Frank Heinrich | Zendy; Andrew Stephen | Zendy

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Uncovering a membrane-distal conformation of KRAS available to recruit RAF to the plasma membrane

Author(s) -

Que N. Van,

César A. López,

Marco Tonelli,

Troy Taylor,

Ben Niu,

Christopher B. Stanley,

Debsindhu Bhowmik,

Timothy H. Tran,

Peter Frank,

Simon Messing,

Patrick Alexander,

Daniel R. Scott,

Xiaoying Ye,

Matt Drew,

Oleg Chertov,

Mathias Lösche,

Arvind Ramanathan,

Michael L. Gross,

Nicolas Hengartner,

William M. Westler,

John L. Markley,

Dhirendra K. Simanshu,

Dwight V. Nissley,

William Gillette,

Dominic Esposito,

Frank McCormick,

S. Gnanakaran,

Frank Heinrich,

Andrew Stephen

Publication year - 2020

Publication title -

proceedings of the national academy of sciences

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.011

H-Index - 771

eISSN - 1091-6490

pISSN - 0027-8424

DOI - 10.1073/pnas.2006504117

Subject(s) - kras , protein kinase domain , microbiology and biotechnology , gtpase , membrane , chemistry , scaffold protein , kinase , biology , cancer research , signal transduction , biochemistry , mutation , mutant , gene

Significance The proto-oncogeneKRAS , a small GTPase, is frequently mutated in pancreatic, colorectal, and lung cancer. These mutations result in elevated levels of the activated guanosine triphosphate-bound form of KRAS. Localized at the plasma membrane, KRAS functions to recruit effectors, predominantly RAF kinase for activation and initiation of the MAPK signaling cascade. Combining computational and biophysical methods we identify a membrane-distal state of the KRAS G-domain that alternates with two previously described membrane-proximal states through dynamic reorganization of the hypervariable region. Comprising about 90% of the ensemble, this membrane-distal state of the G-domain dominates the proximal states and may facilitate KRAS to recruit cytosolic RAF kinase to the membrane by a fly-casting mechanism.

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