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基本情報

登録情報
データベース: PDB / ID: 9for
タイトルStructure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1)
要素
  • Annexin A11
  • TAR DNA-binding protein 43
キーワードPROTEIN FIBRIL / TDP-43 / ANXA11 / amyloid / heteromeric amyloid / FTLD-TDP / FTLD-TDP Type C / neurodegeneration / neurodegenerative disease / dementia / brain / filament
機能・相同性
機能・相同性情報


cytokinetic process / nuclear inner membrane organization / interchromatin granule / perichromatin fibrils / 3'-UTR-mediated mRNA destabilization / specific granule / calcium-dependent phospholipid binding / phosphatidylethanolamine binding / S100 protein binding / vesicle membrane ...cytokinetic process / nuclear inner membrane organization / interchromatin granule / perichromatin fibrils / 3'-UTR-mediated mRNA destabilization / specific granule / calcium-dependent phospholipid binding / phosphatidylethanolamine binding / S100 protein binding / vesicle membrane / azurophil granule / 3'-UTR-mediated mRNA stabilization / intracellular membraneless organelle / phosphatidylserine binding / negative regulation of protein phosphorylation / negative regulation by host of viral transcription / phagocytosis / pre-mRNA intronic binding / phagocytic vesicle / RNA splicing / response to endoplasmic reticulum stress / mRNA 3'-UTR binding / molecular condensate scaffold activity / regulation of circadian rhythm / regulation of protein stability / positive regulation of insulin secretion / spindle / positive regulation of protein import into nucleus / response to calcium ion / mRNA processing / cytoplasmic stress granule / calcium-dependent protein binding / MHC class II protein complex binding / rhythmic process / nuclear envelope / melanosome / regulation of gene expression / midbody / double-stranded DNA binding / : / regulation of apoptotic process / amyloid fibril formation / regulation of cell cycle / nuclear speck / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of gene expression / intracellular membrane-bounded organelle / lipid binding / calcium ion binding / chromatin / mitochondrion / DNA binding / RNA binding / extracellular exosome / nucleoplasm / identical protein binding / nucleus / membrane / plasma membrane / cytosol / cytoplasm
類似検索 - 分子機能
Annexin A11 / TAR DNA-binding protein 43, N-terminal / : / TAR DNA-binding protein 43, N-terminal domain / TAR DNA-binding protein 43, C-terminal / Annexin repeat, conserved site / Annexin repeat signature. / Annexin / Annexin / Annexin repeats ...Annexin A11 / TAR DNA-binding protein 43, N-terminal / : / TAR DNA-binding protein 43, N-terminal domain / TAR DNA-binding protein 43, C-terminal / Annexin repeat, conserved site / Annexin repeat signature. / Annexin / Annexin / Annexin repeats / Annexin repeat / Annexin superfamily / Annexin repeat profile. / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily / Nucleotide-binding alpha-beta plait domain superfamily
類似検索 - ドメイン・相同性
Annexin A11 / TAR DNA-binding protein 43
類似検索 - 構成要素
生物種Homo sapiens (ヒト)
手法電子顕微鏡法 / らせん対称体再構成法 / クライオ電子顕微鏡法 / 解像度: 2.75 Å
データ登録者Arseni, D. / Ryskeldi-Falcon, B.
資金援助 英国, 1件
組織認可番号国
Medical Research Council (MRC, United Kingdom) 英国
引用
ジャーナル: bioRxiv / 年: 2024
タイトル: Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C.
著者: Diana Arseni / Takashi Nonaka / Max H Jacobsen / Alexey G Murzin / Laura Cracco / Sew Y Peak-Chew / Holly J Garringer / Ito Kawakami / Hisaomi Suzuki / Misumoto Onaya / Yuko Saito / Shigeo ...著者: Diana Arseni / Takashi Nonaka / Max H Jacobsen / Alexey G Murzin / Laura Cracco / Sew Y Peak-Chew / Holly J Garringer / Ito Kawakami / Hisaomi Suzuki / Misumoto Onaya / Yuko Saito / Shigeo Murayama / Changiz Geula / Ruben Vidal / Kathy L Newell / Marsel Mesulam / Bernardino Ghetti / Masato Hasegawa / Benjamin Ryskeldi-Falcon
要旨: Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system . Human genetic studies established a causal role for protein ...Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system . Human genetic studies established a causal role for protein assembly in neurodegeneration . However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in electron cryo-microscopy (cryo-EM) have enabled the structures of the protein filaments to be determined from patient brains . All diseases studied to date have been characterised by the self-assembly of a single intracellular protein in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) Types A and B . Here, we used cryo-EM to determine filament structures from the brains of individuals with FTLD-TDP Type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/284-N345 and ANXA11 residues L39-L74 from their respective low-complexity domains (LCDs). Regions of TDP-43 and ANXA11 previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as a ∼22 kDa N-terminal fragment (NTF) lacking the annexin core domain. Immunohistochemistry of brain sections confirmed the co-localisation of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP Type C. This work establishes a central role for ANXA11 in FTLD-TDP Type C. The unprecedented formation of heteromeric amyloid filaments in human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.
#1: ジャーナル: Nature / 年: 2024
タイトル: Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C.
著者: Diana Arseni / Takashi Nonaka / Max H Jacobsen / Alexey G Murzin / Laura Cracco / Sew Y Peak-Chew / Holly J Garringer / Ito Kawakami / Hisaomi Suzuki / Misumoto Onaya / Yuko Saito / Shigeo ...著者: Diana Arseni / Takashi Nonaka / Max H Jacobsen / Alexey G Murzin / Laura Cracco / Sew Y Peak-Chew / Holly J Garringer / Ito Kawakami / Hisaomi Suzuki / Misumoto Onaya / Yuko Saito / Shigeo Murayama / Changiz Geula / Ruben Vidal / Kathy L Newell / Marsel Mesulam / Bernardino Ghetti / Masato Hasegawa / Benjamin Ryskeldi-Falcon /
要旨: Neurodegenerative diseases are characterized by the abnormal filamentous assembly of specific proteins in the central nervous system. Human genetic studies have established a causal role for protein ...Neurodegenerative diseases are characterized by the abnormal filamentous assembly of specific proteins in the central nervous system. Human genetic studies have established a causal role for protein assembly in neurodegeneration. However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in cryo-electron microscopy have enabled the structures of the protein filaments to be determined from the brains of patients. All neurodegenerative diseases studied to date have been characterized by the self-assembly of proteins in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) types A and B. Here we used cryo-electron microscopy to determine filament structures from the brains of individuals with FTLD-TDP type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/G284-N345 and ANXA11 residues L39-Y74 from their respective low-complexity domains. Regions of TDP-43 and ANXA11  that were previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as an approximately 22 kDa N-terminal fragment lacking the annexin core domain. Immunohistochemistry of brain sections showed the colocalization of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP type C. This work establishes a central role for ANXA11 in FTLD-TDP type C. The unprecedented formation of heteromeric amyloid filaments in the human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.
#2: ジャーナル: bioRxiv / 年: 2024
タイトル: Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C.
著者: Diana Arseni / Takashi Nonaka / Max H Jacobsen / Alexey G Murzin / Laura Cracco / Sew Y Peak-Chew / Holly J Garringer / Ito Kawakami / Hisaomi Suzuki / Misumoto Onaya / Yuko Saito / Shigeo ...著者: Diana Arseni / Takashi Nonaka / Max H Jacobsen / Alexey G Murzin / Laura Cracco / Sew Y Peak-Chew / Holly J Garringer / Ito Kawakami / Hisaomi Suzuki / Misumoto Onaya / Yuko Saito / Shigeo Murayama / Changiz Geula / Ruben Vidal / Kathy L Newell / Marsel Mesulam / Bernardino Ghetti / Masato Hasegawa / Benjamin Ryskeldi-Falcon
要旨: Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system . Human genetic studies established a causal role for protein ...Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system . Human genetic studies established a causal role for protein assembly in neurodegeneration . However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in electron cryo-microscopy (cryo-EM) have enabled the structures of the protein filaments to be determined from patient brains . All diseases studied to date have been characterised by the self-assembly of a single intracellular protein in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) Types A and B . Here, we used cryo-EM to determine filament structures from the brains of individuals with FTLD-TDP Type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/284-N345 and ANXA11 residues L39-L74 from their respective low-complexity domains (LCDs). Regions of TDP-43 and ANXA11 previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as a ∼22 kDa N-terminal fragment (NTF) lacking the annexin core domain. Immunohistochemistry of brain sections confirmed the co-localisation of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP Type C. This work establishes a central role for ANXA11 in FTLD-TDP Type C. The unprecedented formation of heteromeric amyloid filaments in human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.
履歴
登録2024年6月12日登録サイト: PDBE / 処理サイト: PDBE
改定 1.02024年7月24日Provider: repository / タイプ: Initial release
改定 1.12024年10月16日Group: Data collection / Database references / Structure summary
カテゴリ: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details
Item: _em_admin.last_update
改定 1.22024年10月23日Group: Data collection / Database references / カテゴリ: citation / citation_author / em_admin / Item: _em_admin.last_update

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構造の表示

構造ビューア分子:
MolmilJmol/JSmol

ダウンロードとリンク

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集合体

登録構造単位
o: TAR DNA-binding protein 43
p: Annexin A11
A: TAR DNA-binding protein 43
B: Annexin A11
C: TAR DNA-binding protein 43
D: Annexin A11
E: TAR DNA-binding protein 43
F: Annexin A11
G: TAR DNA-binding protein 43
H: Annexin A11


分子量 (理論値)分子数
合計 (水以外)49,16410
ポリマ－49,16410
非ポリマー00
水00
1


  • 登録構造と同一
  • 登録者・ソフトウェアが定義した集合体
タイプ名称対称操作数
identity operation1_555x,y,z1

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要素

#1: タンパク質
TAR DNA-binding protein 43 / TDP-43


分子量: 6027.645 Da / 分子数: 5 / 由来タイプ: 天然 / 由来: (天然) Homo sapiens (ヒト) / 組織: Brain / 参照: UniProt: Q13148
#2: タンパク質・ペプチド
Annexin A11 / 56 kDa autoantigen / Annexin XI / Annexin-11 / Calcyclin-associated annexin 50 / CAP-50


分子量: 3805.148 Da / 分子数: 5 / 由来タイプ: 天然 / 由来: (天然) Homo sapiens (ヒト) / 組織: Brain / 参照: UniProt: P50995
Has protein modificationN

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実験情報

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実験

実験手法: 電子顕微鏡法
EM実験試料の集合状態: FILAMENT / ３次元再構成法: らせん対称体再構成法

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試料調製

構成要素名称: Heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1)
タイプ: TISSUE / Entity ID: all / 由来: NATURAL
分子量値: 9.8 kDa/nm / 実験値: NO
由来(天然)生物種: Homo sapiens (ヒト) / 組織: Brain
緩衝液pH: 7.4
試料包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES
詳細: Heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1)
急速凍結凍結剤: ETHANE

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電子顕微鏡撮影

実験機器
モデル: Titan Krios / 画像提供: FEI Company
顕微鏡モデル: TFS KRIOS
電子銃電子線源: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: FLOOD BEAM
電子レンズモード: BRIGHT FIELD / 最大 デフォーカス（公称値）: 2200 nm / 最小 デフォーカス（公称値）: 1000 nm
撮影電子線照射量: 38 e/Å2
フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k)

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解析

EMソフトウェア名称: RELION / バージョン: 5 / カテゴリ: ３次元再構成
CTF補正タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION
らせん対称回転角度/サブユニット: -1.83 ° / 軸方向距離/サブユニット: 4.98 Å / らせん対称軸の対称性: C1
3次元再構成解像度: 2.75 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 18020 / 対称性のタイプ: HELICAL
精密化解像度: 2.75→96.32 Å / Cor.coef. Fo:Fc: 0.819 / SU B: 6.419 / SU ML: 0.128 / ESU R: 0.119
立体化学のターゲット値: MAXIMUM LIKELIHOOD WITH PHASES
詳細: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
Rfactor反射数%反射
Rwork0.30999 --
obs0.30999 37909 100 %
溶媒の処理溶媒モデル: PARAMETERS FOR MASK CACLULATION
原子変位パラメータBiso mean: 55.771 Å2
精密化ステップサイクル: 1 / 合計: 689
拘束条件
Refine-IDタイプDev idealDev ideal target数
ELECTRON MICROSCOPYr_bond_refined_d0.0090.011699
ELECTRON MICROSCOPYr_bond_other_d00.016619
ELECTRON MICROSCOPYr_angle_refined_deg2.1391.723934
ELECTRON MICROSCOPYr_angle_other_deg0.6061.6961409
ELECTRON MICROSCOPYr_dihedral_angle_1_deg8.606598
ELECTRON MICROSCOPYr_dihedral_angle_2_deg1.14651
ELECTRON MICROSCOPYr_dihedral_angle_3_deg13.1461098
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0870.287
ELECTRON MICROSCOPYr_gen_planes_refined0.0080.02908
ELECTRON MICROSCOPYr_gen_planes_other0.0010.02186
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it7.5535.101398
ELECTRON MICROSCOPYr_mcbond_other7.5485.098398
ELECTRON MICROSCOPYr_mcangle_it11.9919.176494
ELECTRON MICROSCOPYr_mcangle_other11.9899.18495
ELECTRON MICROSCOPYr_scbond_it9.2615.768301
ELECTRON MICROSCOPYr_scbond_other9.255.762301
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other13.9210.164441
ELECTRON MICROSCOPYr_long_range_B_refined19.65746.33627
ELECTRON MICROSCOPYr_long_range_B_other19.64346.48628
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS精密化 シェル解像度: 2.75→2.821 Å / Total num. of bins used: 20
Rfactor反射数%反射
Rfree0 0 -
Rwork1.143 2823 -
obs--100 %

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