Structure and dynamics of the full-length lipid-modified H-ras protein in a 1,2-dimyristoylglycero-3-phosphocholine bilayer

A1 Originalartikel i en vetenskaplig tidskrift (referentgranskad)


Interna författare/redaktörer


Publikationens författare: Gorfe AA, Hanzal-Bayer M, Abankwa D, Hancock JF, McCammon JA
Förläggare: AMER CHEMICAL SOC
Publiceringsår: 2007
Tidskrift: Journal of Medicinal Chemistry
Tidskriftsakronym: J MED CHEM
Volym: 50
Nummer: 4
Artikelns första sida, sidnummer: 674
Artikelns sista sida, sidnummer: 684
Antal sidor: 11
ISSN: 0022-2623


Abstrakt

Ras proteins regulate signal transduction processes that control cell growth and proliferation. Their disregulation is a common cause of human tumors. Atomic level structural and dynamical information in a membrane environment is crucial for understanding signaling specificity among Ras isoforms and for the design of selective anti-cancer agents. Here, the structure of the full-length H-Ras protein in complex with a 1,2-dimyristoylglycero-3-phosphocholine (DMPC) bilayer obtained from modeling and all-atom explicit solvent molecular dynamics simulations, as well as experimental validation of the main results, are presented. We find that, in addition to the lipid anchor, H-Ras membrane binding involves direct interaction of residues in the catalytic domain with DMPC phosphates. Two modes of binding (possibly modulated by GTP/GDP exchange) differing in the orientation and bilayer contact of the soluble domain as well as in the participation of the flexible linker in membrane binding are proposed. These results are supported by our initial in vivo experiments. The overall structures of the protein and the bilayer remain similar to those of the isolated components, with few localized structural and dynamical changes. The implications of the results to membrane lateral segregation and other aspects of Ras signaling are discussed.

Senast uppdaterad 2019-05-12 vid 03:33