PDB-6q2j: Cryo-EM structure of extracellular dimeric complex of RET/GFRAL/GDF15

基本情報

• 登録情報: データベース: PDB / ID: 6q2j
• タイトル: Cryo-EM structure of extracellular dimeric complex of RET/GFRAL/GDF15

要素

• GDNF family receptor alpha-like
• Growth/differentiation factor 15
• Proto-oncogene tyrosine-protein kinase receptor Ret

• キーワード: SIGNALING PROTEIN / RET / receptor tyrosine kinase / cryo-EM

機能・相同性

分子機能:

negative regulation of growth hormone receptor signaling pathway / GDF15-GFRAL signaling pathway / response to metformin / reduction of food intake in response to dietary excess / glial cell-derived neurotrophic factor receptor activity / Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / posterior midgut development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / membrane protein proteolysis / positive regulation of peptidyl-serine phosphorylation of STAT protein / Formation of the ureteric bud / positive regulation of neuron maturation / negative regulation of leukocyte migration / Formation of the nephric duct / enteric nervous system development / neuron cell-cell adhesion / positive regulation of fatty acid oxidation / negative regulation of appetite / cellular response to chemical stress / innervation / plasma membrane protein complex / neuron maturation / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / stress-activated protein kinase signaling cascade / positive regulation of cell adhesion mediated by integrin / neural crest cell migration / ureteric bud development / negative regulation of multicellular organism growth / response to pain / regulation of axonogenesis / positive regulation of myoblast fusion / negative regulation of SMAD protein signal transduction / homophilic cell adhesion via plasma membrane adhesion molecules / positive regulation of cell size / RET signaling / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / regulation of cell adhesion / cellular response to retinoic acid / NPAS4 regulates expression of target genes / transmembrane receptor protein tyrosine kinase activity / transforming growth factor beta receptor signaling pathway / cytokine activity / axon guidance / negative regulation of transforming growth factor beta receptor signaling pathway / growth factor activity / hormone activity / receptor protein-tyrosine kinase / receptor tyrosine kinase binding / positive regulation of neuron projection development / activation of cysteine-type endopeptidase activity involved in apoptotic process / MAPK cascade / actin cytoskeleton / cell-cell signaling / retina development in camera-type eye / nervous system development / signaling receptor activity / RAF/MAP kinase cascade / protein tyrosine kinase activity / negative regulation of neuron apoptotic process / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / early endosome / receptor complex / endosome membrane / positive regulation of cell migration / response to xenobiotic stimulus / external side of plasma membrane / axon / protein phosphorylation / focal adhesion / neuronal cell body / calcium ion binding / dendrite / positive regulation of gene expression / positive regulation of DNA-templated transcription / Golgi apparatus / signal transduction / protein homodimerization activity / extracellular space / extracellular exosome / extracellular region / nucleoplasm / ATP binding / nucleus / plasma membrane / cytoplasm

ドメイン・相同性:

Glial cell line-derived neurotrophic factor receptor / GDNF receptor alpha / GDNF/GAS1 / GDNF/GAS1 domain / GDNF/GAS1 domain / Tyrosine-protein kinase, Ret receptor / Tyrosine-protein kinase receptor Ret, cadherin like domain 3 / Ret, cadherin like domain 1 / RET, cadherin-like domain 4 / RET Cadherin like domain 1 / RET Cadherin like domain 3 / RET Cadherin like domain 4 / Transforming growth factor-beta-related / Transforming growth factor-beta (TGF-beta) family / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain / TGF-beta family profile. / Cadherin domain / Cadherins domain profile. / Cadherin-like / Cadherin-like superfamily / Cystine-knot cytokine / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily

構成要素:

Proto-oncogene tyrosine-protein kinase receptor Ret / GDNF family receptor alpha-like / Growth/differentiation factor 15

• 生物種: Homo sapiens (ヒト)
• 手法: 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 4.1 Å
• データ登録者: Li, J. / Shang, G.J. / Chen, Y.J. / Brautigam, C.A. / Liou, J. / Zhang, X.W. / Bai, X.C.
• 引用: ジャーナル: Elife / 年: 2019; タイトル: Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands.; 著者: Jie Li / Guijun Shang / Yu-Ju Chen / Chad A Brautigam / Jen Liou / Xuewu Zhang / Xiao-Chen Bai / ; 要旨: RET is a receptor tyrosine kinase (RTK) that plays essential roles in development and has been implicated in several human diseases. Different from most of RTKs, RET requires not only its cognate ligands but also co-receptors for activation, the mechanisms of which remain unclear due to lack of high-resolution structures of the ligand/co-receptor/receptor complexes. Here, we report cryo-EM structures of the extracellular region ternary complexes of GDF15/GFRAL/RET, GDNF/GFRα1/RET, NRTN/GFRα2/RET and ARTN/GFRα3/RET. These structures reveal that all the four ligand/co-receptor pairs, while using different atomic interactions, induce a specific dimerization mode of RET that is poised to bring the two kinase domains into close proximity for cross-phosphorylation. The NRTN/GFRα2/RET dimeric complex further pack into a tetrameric assembly, which is shown by our cell-based assays to regulate the endocytosis of RET. Our analyses therefore reveal both the common mechanism and diversification in the activation of RET by different ligands.

履歴

登録	2019年8月8日	登録サイト: RCSB / 処理サイト: RCSB
改定 1.0	2019年10月2日	Provider: repository / タイプ: Initial release
改定 1.1	2020年7月29日	Group: Data collection / Derived calculations / Structure summary カテゴリ: chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen Item: _chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id 解説: Carbohydrate remediation / Provider: repository / タイプ: Remediation

集合体

登録構造単位

A: Growth/differentiation factor 15

C: GDNF family receptor alpha-like

E: Proto-oncogene tyrosine-protein kinase receptor Ret

B: Growth/differentiation factor 15

D: GDNF family receptor alpha-like

F: Proto-oncogene tyrosine-protein kinase receptor Ret

ヘテロ分子

概要:

• 250 kDa, 6 ポリマー

構成要素の詳細:

	分子量 (理論値)	分子数
合計 (水以外)	249,619	28
ポリマ－	246,201	6
非ポリマー	3,418	22
水	0	0

1

概要:

• 登録構造と同一
• 登録者が定義した集合体
• 根拠: gel filtration

対称操作:

タイプ	名称	対称操作	数
identity operation	1_555		1

要素

#1: タンパク質

A B Growth/differentiation factor 15 / GDF-15 / Macrophage inhibitory cytokine 1 / MIC-1 / NSAID-activated gene 1 protein / NAG-1 / NSAID-regulated gene 1 protein / NRG-1 / Placental TGF-beta / Placental bone morphogenetic protein / Prostate differentiation factor

詳細:

分子量: 14879.113 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GDF15, MIC1, PDF, PLAB, PTGFB / 発現宿主: Escherichia coli (大腸菌) / 参照: UniProt: Q99988

#2: タンパク質

C D GDNF family receptor alpha-like

詳細:

分子量: 39120.598 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現)