@article{a51a2eed62394bd29a32b2639f395b7b,
title = "The Structure of the MAP2K MEK6 Reveals an Autoinhibitory Dimer",
abstract = "MAP2Ks are dual-specificity protein kinases functioning at the center of three-tiered MAP kinase modules. The structure of the kinase domain of the MAP2K MEK6 with phosphorylation site mimetic aspartic acid mutations (MEK6/ΔN/DD) has been solved at 2.3 {\AA} resolution. The structure reveals an autoinhibited elongated ellipsoidal dimer. The enzyme adopts an inactive conformation, based upon structural queues, despite the phosphomimetic mutations. Gel filtration and small-angle X-ray scattering analysis confirm that the crystallographically observed ellipsoidal dimer is a feature of MEK6/ΔN/DD and full-length unphosphorylated wild-type MEK6 in solution. The interface includes the phosphate binding ribbon of each subunit, part of the activation loop, and a rare {"}arginine stack{"} between symmetry-related arginine residues in the N-terminal lobe. The autoinhibited structure likely confers specificity on active MAP2Ks. The dimer may also serve the function in unphosphorylated MEK6 of preventing activation loop phosphorylation by inappropriate kinases.",
keywords = "PROTEINS, SIGNALING",
author = "Xiaoshan Min and Radha Akella and Haixia He and Humphreys, {John M.} and Tsutakawa, {Susan E.} and Lee, {Seung Jae} and Tainer, {John A.} and Cobb, {Melanie H.} and Goldsmith, {Elizabeth J.}",
note = "Funding Information: We thank Diana Tomchick and Mischa Machius and the staff at Argonne National Laboratory for help in synchrotron data collection. We thank Luke Rice for help in analytical gel filtration. We thank beamline scientist Michal Hammel for aiding expert SAXS analysis. This research was supported by a grant from the NIH (DK46993) and funding I1128 and I1243 from the Welch Foundation. The U.S. Department of Energy, Office of Biological and Environmental Research, under contract number W-31-109-ENG-38, supported use of the Argonne National Laboratory Structural Biology Center beamlines at the Advanced Photon Source. X-ray scattering technologies at the Lawrence Berkeley National Laboratory SIBYLS beamline of the Advanced Light Source (ALS) are supported by the DOE program Integrated Diffraction Analysis Technologies (IDAT) under contract DE-AC02-05CH11231 with the U.S. Department of Energy. Applications of SAXS and crystallography at the ALS relevant to human cancers are supported in part by National Cancer Institute grant CA92584. ",
year = "2009",
month = jan,
day = "14",
doi = "10.1016/j.str.2008.11.007",
language = "English (US)",
volume = "17",
pages = "96--104",
journal = "Structure",
issn = "0969-2126",
publisher = "Cell Press",
number = "1",
}