National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01NS088367
米国
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
R01AI107121
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01NS092662
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
F31NS083336
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
F32NS106730
米国
National Institutes of Health/National Cancer Institute (NIH/NCI)
T32CA060395
米国
引用
ジャーナル: Elife / 年: 2020 タイトル: Antibody escape by polyomavirus capsid mutation facilitates neurovirulence. 著者: Matthew D Lauver / Daniel J Goetschius / Colleen S Netherby-Winslow / Katelyn N Ayers / Ge Jin / Daniel G Haas / Elizabeth L Frost / Sung Hyun Cho / Carol M Bator / Stephanie M Bywaters / ...著者: Matthew D Lauver / Daniel J Goetschius / Colleen S Netherby-Winslow / Katelyn N Ayers / Ge Jin / Daniel G Haas / Elizabeth L Frost / Sung Hyun Cho / Carol M Bator / Stephanie M Bywaters / Neil D Christensen / Susan L Hafenstein / Aron E Lukacher / 要旨: JCPyV polyomavirus, a member of the human virome, causes progressive multifocal leukoencephalopathy (PML), an oft-fatal demyelinating brain disease in individuals receiving immunomodulatory therapies. ...JCPyV polyomavirus, a member of the human virome, causes progressive multifocal leukoencephalopathy (PML), an oft-fatal demyelinating brain disease in individuals receiving immunomodulatory therapies. Mutations in the major viral capsid protein, VP1, are common in JCPyV from PML patients (JCPyV-PML) but whether they confer neurovirulence or escape from virus-neutralizing antibody (nAb) in vivo is unknown. A mouse polyomavirus (MuPyV) with a sequence-equivalent JCPyV-PML VP1 mutation replicated poorly in the kidney, a major reservoir for JCPyV persistence, but retained the CNS infectivity, cell tropism, and neuropathology of the parental virus. This mutation rendered MuPyV resistant to a monoclonal Ab (mAb), whose specificity overlapped the endogenous anti-VP1 response. Using cryo-EM and a custom sub-particle refinement approach, we resolved an MuPyV:Fab complex map to 3.2 Å resolution. The structure revealed the mechanism of mAb evasion. Our findings demonstrate convergence between nAb evasion and CNS neurovirulence in vivo by a frequent JCPyV-PML VP1 mutation.
全体 : 8A7H5 Fab light chain, 8A7H5 Fab heavy chain, Capsid protein VP1
全体
名称: 8A7H5 Fab light chain, 8A7H5 Fab heavy chain, Capsid protein VP1
要素
複合体: 8A7H5 Fab light chain, 8A7H5 Fab heavy chain, Capsid protein VP1
複合体: 8A7H5 Fab light chain, 8A7H5 Fab heavy chain
タンパク質・ペプチド: 8A7H5 Fab light chain
タンパク質・ペプチド: 8A7H5 Fab heavy chain
ウイルス: Murine polyomavirus strain A2 (ウイルス)
タンパク質・ペプチド: Capsid protein VP1カプシド
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超分子 #1: 8A7H5 Fab light chain, 8A7H5 Fab heavy chain, Capsid protein VP1
超分子
名称: 8A7H5 Fab light chain, 8A7H5 Fab heavy chain, Capsid protein VP1 タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all / 詳細: Fab fragment generated from rat IgG
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超分子 #2: 8A7H5 Fab light chain, 8A7H5 Fab heavy chain
超分子
名称: 8A7H5 Fab light chain, 8A7H5 Fab heavy chain / タイプ: complex / ID: 2 / 親要素: 1 / 含まれる分子: #1-#2
モデルのタイプ: INSILICO MODEL In silico モデル: Initial model generated ab initio in cryoSPARC with I1 symmetry imposed. Initial model for subvolume reconstruction was generated using 10,000 subparticles using ISECC_subpaticle_extract.
初期 角度割当
タイプ: MAXIMUM LIKELIHOOD 詳細: I1-constrained angles for whole capsid derived using 3D Refinement in RELION. Subparticle initial angles and offsets were mathematically derived from icosahedral parameters using ISECC_subpaticle_extract.