+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-29341 | |||||||||
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タイトル | Cryo-EM structure of Rab29-LRRK2 complex in the LRRK2 dimer state | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | Cryo-EM / Parkinson's disease / Kinase / LRRK2 / Rab GTPases / Activation / HYDROLASE | |||||||||
機能・相同性 | 機能・相同性情報 protein localization to ciliary membrane / peroxidase inhibitor activity / caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / regulation of branching morphogenesis of a nerve / beta-catenin destruction complex binding / regulation of kidney size / regulation of neuron maturation ...protein localization to ciliary membrane / peroxidase inhibitor activity / caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / regulation of branching morphogenesis of a nerve / beta-catenin destruction complex binding / regulation of kidney size / regulation of neuron maturation / tangential migration from the subventricular zone to the olfactory bulb / protein localization to endoplasmic reticulum exit site / GTP-dependent protein kinase activity / regulation of neuroblast proliferation / regulation of ER to Golgi vesicle-mediated transport / negative regulation of late endosome to lysosome transport / regulation of mitochondrial depolarization / negative regulation of protein targeting to mitochondrion / regulation of synaptic vesicle transport / regulation of lysosomal lumen pH / positive regulation of dopamine receptor signaling pathway / amphisome / regulation of CAMKK-AMPK signaling cascade / cytoplasmic side of mitochondrial outer membrane / regulation of protein kinase A signaling / co-receptor binding / modulation by host of viral process / mitochondrion localization / regulation of retrograde transport, endosome to Golgi / negative regulation of excitatory postsynaptic potential / regulation of dopamine receptor signaling pathway / negative regulation of autophagosome assembly / positive regulation of microglial cell activation / neuron projection arborization / positive regulation of synaptic vesicle endocytosis / JUN kinase kinase kinase activity / RAB geranylgeranylation / olfactory bulb development / positive regulation of intracellular protein transport / regulation of dendritic spine morphogenesis / melanosome organization / striatum development / multivesicular body, internal vesicle / protein localization to mitochondrion / protein localization to membrane / cis-Golgi network / cellular response to dopamine / endoplasmic reticulum organization / positive regulation of protein autoubiquitination / presynaptic cytosol / retrograde transport, endosome to Golgi / positive regulation of programmed cell death / vacuole / Wnt signalosome / cellular detoxification / GTP metabolic process / regulation of canonical Wnt signaling pathway / negative regulation of protein processing / negative regulation of GTPase activity / syntaxin-1 binding / regulation of reactive oxygen species metabolic process / exploration behavior / protein kinase A binding / regulation of locomotion / regulation of synaptic vesicle exocytosis / clathrin binding / PTK6 promotes HIF1A stabilization / Golgi-associated vesicle / negative regulation of macroautophagy / neuromuscular junction development / intracellular vesicle / lysosome organization / dynein complex binding / positive regulation of receptor recycling / positive regulation of T cell receptor signaling pathway / regulation of mitochondrial fission / intracellular distribution of mitochondria / autolysosome / Golgi organization / positive regulation of nitric-oxide synthase biosynthetic process / locomotory exploration behavior / endoplasmic reticulum exit site / kinesin binding / microvillus / Rho protein signal transduction / MAP kinase kinase kinase activity / positive regulation of protein kinase activity / endomembrane system / cellular response to manganese ion / canonical Wnt signaling pathway / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / positive regulation of autophagy / phosphorylation / JNK cascade / regulation of synaptic transmission, glutamatergic / synapse assembly / dendrite cytoplasm / cellular response to starvation / GTPase activator activity / tubulin binding 類似検索 - 分子機能 | |||||||||
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: 3.88 Å | |||||||||
データ登録者 | Zhu H / Sun J | |||||||||
資金援助 | 米国, 1件
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引用 | ジャーナル: Science / 年: 2023 タイトル: Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2. 著者: Hanwen Zhu / Francesca Tonelli / Martin Turk / Alan Prescott / Dario R Alessi / Ji Sun / 要旨: Gain-of-function mutations in , which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles ...Gain-of-function mutations in , which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles and activated by Rab29, a Rab guanosine triphosphatase encoded in the locus. We present cryo-electron microscopy structures of Rab29-LRRK2 complexes in three oligomeric states, providing key snapshots during LRRK2 recruitment and activation. Rab29 induces an unexpected tetrameric assembly of LRRK2, formed by two kinase-active central protomers and two kinase-inactive peripheral protomers. The central protomers resemble the active-like state trapped by the type I kinase inhibitor DNL201, a compound that underwent a phase 1 clinical trial. Our work reveals the structural mechanism of LRRK2 spatial regulation and provides insights into LRRK2 inhibitor design for Parkinson's disease treatment. #1: ジャーナル: bioRxiv / 年: 2022 タイトル: Structural basis of human LRRK2 membrane recruitment and activation 著者: Zhu H / Tonelli F / Alessi D / Sun J | |||||||||
履歴 |
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-構造の表示
添付画像 |
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-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_29341.map.gz | 398.8 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-29341-v30.xml emd-29341.xml | 18.3 KB 18.3 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_29341.png | 52.9 KB | ||
Filedesc metadata | emd-29341.cif.gz | 7.2 KB | ||
その他 | emd_29341_half_map_1.map.gz emd_29341_half_map_2.map.gz | 391.8 MB 391.8 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-29341 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-29341 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_29341_validation.pdf.gz | 824.5 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_29341_full_validation.pdf.gz | 824 KB | 表示 | |
XML形式データ | emd_29341_validation.xml.gz | 17.9 KB | 表示 | |
CIF形式データ | emd_29341_validation.cif.gz | 21.2 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-29341 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-29341 | HTTPS FTP |
-関連構造データ
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_29341.map.gz / 形式: CCP4 / 大きさ: 421.9 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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投影像・断面図 | 画像のコントロール
画像は Spider により作成 | ||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 1.06 Å | ||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-ハーフマップ: #2
ファイル | emd_29341_half_map_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #1
ファイル | emd_29341_half_map_2.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-試料の構成要素
-全体 : Rab29-LRRK2
全体 | 名称: Rab29-LRRK2 |
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要素 |
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-超分子 #1: Rab29-LRRK2
超分子 | 名称: Rab29-LRRK2 / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#2 |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
-分子 #1: Ras-related protein Rab-7L1
分子 | 名称: Ras-related protein Rab-7L1 / タイプ: protein_or_peptide / ID: 1 / コピー数: 2 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 20.239076 KDa |
組換発現 | 生物種: Escherichia coli (大腸菌) |
配列 | 文字列: MGSRDHLFKV LVVGDAAVGK TSLVQRYSQD SFSKHYKSTV GVDFALKVLQ WSDYEIVRLQ LWDIAGLERF AAMTRLYYRD ASACVIMFD VTNATTFSNS QRWKQDLDSK LTLPNGEPVP CLLLANKCDL SPWAVSRDQI DRFSKENGFT GWTETSVKEN K NINEAMRV LIEKMMRNS UniProtKB: Ras-related protein Rab-7L1 |
-分子 #2: Leucine-rich repeat serine/threonine-protein kinase 2
分子 | 名称: Leucine-rich repeat serine/threonine-protein kinase 2 タイプ: protein_or_peptide / ID: 2 / コピー数: 2 / 光学異性体: LEVO / EC番号: non-specific serine/threonine protein kinase |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 286.427656 KDa |
組換発現 | 生物種: Homo sapiens (ヒト) |
配列 | 文字列: MASGSCQGCE EDEETLKKLI VRLNNVQEGK QIETLVQILE DLLVFTYSEH ASKLFQGKNI HVPLLIVLDS YMRVASVQQV GWSLLCKLI EVCPGTMQSL MGPQDVGNDW EVLGVHQLIL KMLTVHNASV NLSVIGLKTL DLLLTSGKIT LLILDEESDI F MLIFDAMH ...文字列: MASGSCQGCE EDEETLKKLI VRLNNVQEGK QIETLVQILE DLLVFTYSEH ASKLFQGKNI HVPLLIVLDS YMRVASVQQV GWSLLCKLI EVCPGTMQSL MGPQDVGNDW EVLGVHQLIL KMLTVHNASV NLSVIGLKTL DLLLTSGKIT LLILDEESDI F MLIFDAMH SFPANDEVQK LGCKALHVLF ERVSEEQLTE FVENKDYMIL LSALTNFKDE EEIVLHVLHC LHSLAIPCNN VE VLMSGNV RCYNIVVEAM KAFPMSERIQ EVSCCLLHRL TLGNFFNILV LNEVHEFVVK AVQQYPENAA LQISALSCLA LLT ETIFLN QDLEEKNENQ ENDDEGEEDK LFWLEACYKA LTWHRKNKHV QEAACWALNN LLMYQNSLHE KIGDEDGHFP AHRE VMLSM LMHSSSKEVF QASANALSTL LEQNVNFRKI LLSKGIHLNV LELMQKHIHS PEVAESGCKM LNHLFEGSNT SLDIM AAVV PKILTVMKRH ETSLPVQLEA LRAILHFIVP GMPEESREDT EFHHKLNMVK KQCFKNDIHK LVLAALNRFI GNPGIQ KCG LKVISSIVHF PDALEMLSLE GAMDSVLHTL QMYPDDQEIQ CLGLSLIGYL ITKKNVFIGT GHLLAKILVS SLYRFKD VA EIQTKGFQTI LAILKLSASF SKLLVHHSFD LVIFHQMSSN IMEQKDQQFL NLCCKCFAKV AMDDYLKNVM LERACDQN N SIMVECLLLL GADANQAKEG SSLICQVCEK ESSPKLVELL LNSGSREQDV RKALTISIGK GDSQIISLLL RRLALDVAN NSICLGGFCI GKVEPSWLGP LFPDKTSNLR KQTNIASTLA RMVIRYQMKS AVEEGTASGS DGNFSEDVLS KFDEWTFIPD SSMDSVFAQ SDDLDSEGSE GSFLVKKKSN SISVGEFYRD AVLQRCSPNL QRHSNSLGPI FDHEDLLKRK RKILSSDDSL R SSKLQSHM RHSDSISSLA SEREYITSLD LSANELRDID ALSQKCCISV HLEHLEKLEL HQNALTSFPQ QLCETLKSLT HL DLHSNKF TSFPSYLLKM SCIANLDVSR NDIGPSVVLD PTVKCPTLKQ FNLSYNQLSF VPENLTDVVE KLEQLILEGN KIS GICSPL RLKELKILNL SKNHISSLSE NFLEACPKVE SFSARMNFLA AMPFLPPSMT ILKLSQNKFS CIPEAILNLP HLRS LDMSS NDIQYLPGPA HWKSLNLREL LFSHNQISIL DLSEKAYLWS RVEKLHLSHN KLKEIPPEIG CLENLTSLDV SYNLE LRSF PNEMGKLSKI WDLPLDELHL NFDFKHIGCK AKDIIRFLQQ RLKKAVPYNR MKLMIVGNTG SGKTTLLQQL MKTKKS DLG MQSATVGIDV KDWPIQIRDK RKRDLVLNVW DFAGREEFYS THPHFMTQRA LYLAVYDLSK GQAEVDAMKP WLFNIKA RA SSSPVILVGT HLDVSDEKQR KACMSKITKE LLNKRGFPAI RDYHFVNATE ESDALAKLRK TIINESLNFK IRDQLVVG Q LIPDCYVELE KIILSERKNV PIEFPVIDRK RLLQLVRENQ LQLDENELPH AVHFLNESGV LLHFQDPALQ LSDLYFVEP KWLCKIMAQI LTVKVEGCPK HPKGIISRRD VEKFLSKKRK FPKNYMTQYF KLLEKFQIAL PIGEEYLLVP SSLSDHRPVI ELPHCENSE IIIRLYEMPY FPMGFWSRLI NRLLEISPYM LSGRERALRP NRMYWRQGIY LNWSPEAYCL VGSEVLDNHP E SFLKITVP SCRKGCILLG QVVDHIDSLM EEWFPGLLEI DICGEGETLL KKWALYSFND GEEHQKILLD DLMKKAEEGD LL VNPDQPR LTIPISQIAP DLILADLPRN IMLNNDELEF EQAPEFLLGD GSFGSVYRAA YEGEEVAVKI FNKHTSLRLL RQE LVVLCH LHHPSLISLL AAGIRPRMLV MELASKGSLD RLLQQDKASL TRTLQHRIAL HVADGLRYLH SAMIIYRDLK PHNV LLFTL YPNAAIIAKI ADYGIAQYCC RMGIKTSEGT PGFRAPEVAR GNVIYNQQAD VYSFGLLLYD ILTTGGRIVE GLKFP NEFD ELEIQGKLPD PVKEYGCAPW PMVEKLIKQC LKENPQERPT SAQVFDILNS AELVCLTRRI LLPKNVIVEC MVATHH NSR NASIWLGCGH TDRGQLSFLD LNTEGYTSEE VADSRILCLA LVHLPVEKES WIVSGTQSGT LLVINTEDGK KRHTLEK MT DSVTCLYCNS FSKQSKQKNF LLVGTADGKL AIFEDKTVKL KGAAPLKILN IGNVSTPLMC LSESTNSTER NVMWGGCG T KIFSFSNDFT IQKLIETRTS QLFSYAAFSD SNIITVVVDT ALYIAKQNSP VVEVWDKKTE KLCGLIDCVH FLREVTVKE NKESKHKMSY SGRVKTLCLQ KNTALWIGTG GGHILLLDLS TRRLIRVIYN FCNSVRVMMT AQLGSLKNVM LVLGYNRKNT EGTQKQKEI QSCLTVWDIN LPHEVQNLEK HIEVRKELAE KMRRTSVE UniProtKB: Leucine-rich repeat serine/threonine-protein kinase 2 |
-分子 #3: GUANOSINE-5'-DIPHOSPHATE
分子 | 名称: GUANOSINE-5'-DIPHOSPHATE / タイプ: ligand / ID: 3 / コピー数: 2 / 式: GDP |
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分子量 | 理論値: 443.201 Da |
Chemical component information | ChemComp-GDP: |
-分子 #4: ADENOSINE-5'-TRIPHOSPHATE
分子 | 名称: ADENOSINE-5'-TRIPHOSPHATE / タイプ: ligand / ID: 4 / コピー数: 2 / 式: ATP |
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分子量 | 理論値: 507.181 Da |
Chemical component information | ChemComp-ATP: |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
緩衝液 | pH: 8 |
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凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 平均電子線量: 58.8 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | 照射モード: OTHER / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 1.8 µm / 最小 デフォーカス(公称値): 0.6 µm |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
-画像解析
初期モデル | モデルのタイプ: NONE |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 3.88 Å / 解像度の算出法: OTHER / ソフトウェア - 名称: cryoSPARC / 使用した粒子像数: 96502 |
初期 角度割当 | タイプ: OTHER |
最終 角度割当 | タイプ: OTHER |