登録情報 データベース : EMDB / ID : EMD-14219 ダウンロードとリンクタイトル Composite map of the open conformation of neurofibromin マップデータComposite map of neurofibromin in open conformation 詳細 試料複合体 : Homodimer of Neurofibrominタンパク質・ペプチド : Isoform I of Neurofibrominリガンド : 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE 詳細 キーワード Signalling protein / Homodimer / Neurofibromatosis / GAP / SIGNALING PROTEIN機能・相同性 機能・相同性情報分子機能 ドメイン・相同性 構成要素
positive regulation of mast cell apoptotic process / negative regulation of Rac protein signal transduction / regulation of glial cell differentiation / observational learning / Schwann cell migration / negative regulation of Schwann cell migration / vascular associated smooth muscle cell migration / amygdala development / gamma-aminobutyric acid secretion, neurotransmission / negative regulation of mast cell proliferation ... positive regulation of mast cell apoptotic process / negative regulation of Rac protein signal transduction / regulation of glial cell differentiation / observational learning / Schwann cell migration / negative regulation of Schwann cell migration / vascular associated smooth muscle cell migration / amygdala development / gamma-aminobutyric acid secretion, neurotransmission / negative regulation of mast cell proliferation / mast cell apoptotic process / Schwann cell proliferation / vascular associated smooth muscle cell proliferation / mast cell proliferation / glutamate secretion, neurotransmission / negative regulation of Schwann cell proliferation / negative regulation of leukocyte migration / negative regulation of vascular associated smooth muscle cell migration / positive regulation of adenylate cyclase activity / regulation of cell-matrix adhesion / forebrain morphogenesis / negative regulation of neurotransmitter secretion / hair follicle maturation / cell communication / regulation of blood vessel endothelial cell migration / smooth muscle tissue development / camera-type eye morphogenesis / negative regulation of oligodendrocyte differentiation / sympathetic nervous system development / myelination in peripheral nervous system / myeloid leukocyte migration / peripheral nervous system development / phosphatidylcholine binding / metanephros development / phosphatidylethanolamine binding / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of Ras protein signal transduction / collagen fibril organization / regulation of bone resorption / regulation of long-term synaptic potentiation / neural tube development / endothelial cell proliferation / forebrain astrocyte development / artery morphogenesis / regulation of postsynapse organization / regulation of synaptic transmission, GABAergic / negative regulation of neuroblast proliferation / negative regulation of MAPK cascade / adrenal gland development / negative regulation of protein import into nucleus / pigmentation / negative regulation of cell-matrix adhesion / spinal cord development / regulation of GTPase activity / Rac protein signal transduction / oligodendrocyte differentiation / negative regulation of osteoclast differentiation / negative regulation of endothelial cell proliferation / RAS signaling downstream of NF1 loss-of-function variants / negative regulation of astrocyte differentiation / extrinsic apoptotic signaling pathway via death domain receptors / neuroblast proliferation / regulation of angiogenesis / Schwann cell development / negative regulation of stem cell proliferation / negative regulation of fibroblast proliferation / skeletal muscle tissue development / extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of endothelial cell proliferation / extracellular matrix organization / negative regulation of angiogenesis / negative regulation of cell migration / phosphatidylinositol 3-kinase/protein kinase B signal transduction / GTPase activator activity / regulation of ERK1 and ERK2 cascade / osteoclast differentiation / positive regulation of GTPase activity / liver development / negative regulation of MAP kinase activity / stem cell proliferation / long-term synaptic potentiation / regulation of long-term neuronal synaptic plasticity / negative regulation of protein kinase activity / wound healing / visual learning / brain development / cerebral cortex development / cognition / Regulation of RAS by GAPs / osteoblast differentiation / protein import into nucleus / MAPK cascade / positive regulation of neuron apoptotic process / presynapse / heart development / cellular response to heat / fibroblast proliferation / actin cytoskeleton organization / regulation of gene expression 類似検索 - 分子機能 Ras GTPase-activating protein / Ras GTPase-activating protein, conserved site / Ras GTPase-activating proteins domain signature. / GTPase-activator protein for Ras-like GTPase / Ras GTPase-activating proteins profile. / GTPase-activator protein for Ras-like GTPases / Ras GTPase-activating domain / Divergent CRAL/TRIO domain / CRAL-TRIO lipid binding domain profile. / Domain in homologues of a S. cerevisiae phosphatidylinositol transfer protein (Sec14p) ... Ras GTPase-activating protein / Ras GTPase-activating protein, conserved site / Ras GTPase-activating proteins domain signature. / GTPase-activator protein for Ras-like GTPase / Ras GTPase-activating proteins profile. / GTPase-activator protein for Ras-like GTPases / Ras GTPase-activating domain / Divergent CRAL/TRIO domain / CRAL-TRIO lipid binding domain profile. / Domain in homologues of a S. cerevisiae phosphatidylinositol transfer protein (Sec14p) / CRAL-TRIO lipid binding domain / CRAL-TRIO lipid binding domain superfamily / Rho GTPase activation protein / PH-like domain superfamily / Armadillo-type fold 類似検索 - ドメイン・相同性生物種 Homo sapiens (ヒト)手法 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度 : 3.7 Å 詳細 データ登録者Chaker-Margot M / Scheffzek K 資金援助 スイス, 1件 詳細 詳細を隠すOrganization Grant number 国 Human Frontier Science Program (HFSP) スイス
引用ジャーナル : Mol Cell / 年 : 2022タイトル : Structural basis of activation of the tumor suppressor protein neurofibromin.著者 : Malik Chaker-Margot / Sebastiaan Werten / Theresia Dunzendorfer-Matt / Stefan Lechner / Angela Ruepp / Klaus Scheffzek / Timm Maier / 要旨 : Mutations in the NF1 gene cause the familial genetic disease neurofibromatosis type I, as well as predisposition to cancer. The NF1 gene product, neurofibromin, is a GTPase-activating protein and ... Mutations in the NF1 gene cause the familial genetic disease neurofibromatosis type I, as well as predisposition to cancer. The NF1 gene product, neurofibromin, is a GTPase-activating protein and acts as a tumor suppressor by negatively regulating the small GTPase, Ras. However, structural insights into neurofibromin activation remain incompletely defined. Here, we provide cryoelectron microscopy (cryo-EM) structures that reveal an extended neurofibromin homodimer in two functional states: an auto-inhibited state with occluded Ras-binding site and an asymmetric open state with an exposed Ras-binding site. Mechanistically, the transition to the active conformation is stimulated by nucleotide binding, which releases a lock that tethers the catalytic domain to an extended helical repeat scaffold in the occluded state. Structure-guided mutational analysis supports functional relevance of allosteric control. Disease-causing mutations are mapped and primarily impact neurofibromin stability. Our findings suggest a role for nucleotides in neurofibromin regulation and may lead to therapeutic modulation of Ras signaling. 履歴 登録 2022年2月1日 - ヘッダ(付随情報) 公開 2022年3月30日 - マップ公開 2022年3月30日 - 更新 2024年7月17日 - 現状 2024年7月17日 処理サイト : PDBe / 状態 : 公開
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