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| 1 | Mechanical activation of spike fosters SARS-CoV-2 viral infection显示文摘The outbreak of SARS-CoV-2(SARS2)has caused a global COVID-19 pandemic.The spike protein of SARS2(SARS2-S)recognizes host receptors,including ACE2,to initiate viral entry in a complex biomechanical environment.Here,we reveal that tensile force,generated by bending of the host cell membrane,strengthens spike recognition of ACE2 and accelerates the detachment of spike’s S1 subunit from the S2 subunit to rapidly prime the viral fusion machinery.Mechanistically,such mechano-activation is fulfilled by force-induced opening and rotation of spike’s receptor-binding domain to prolong the bond lifetime of spike/ACE2 binding,up to 4 times longer than that of SARS-S binding with ACE2 under 10 pN force application,and subsequently by force-accelerated S1/S2 detachment which is up to~103 times faster than that in the no-force condition.Interestingly,the SARS2-S D614G mutant,a more infectious variant,shows 3-time stronger force-dependent ACE2 binding and 35-time faster force-induced S1/S2 detachment.We also reveal that an anti-S1/S2 non-RBD-blocking antibody that was derived from convalescent COVID-19 patients with potent neutralizing capability can reduce S1/S2 detachment by 3×106 times under force.Our study sheds light on the mechano-chemistry of spike activation and on developing a non-RBD-blocking but S1/S2-locking therapeutic strategy to prevent SARS2 invasion. | Wei Hu Yong Zhang Panyu Fei Tongtong Zhang Danmei Yao Yufei Gao Jia Liu Hui Chen Qiao Lu Tenny Mudianto Xinrui Zhang Chuxuan Xiao Yang Ye Qiming Sun Jing Zhang Qi Xie Pei-Hui Wang Jun Wang Zhenhai Li Jizhong Lou Wei Chen | 2021 | Cell Research2021，31，10： | 2 |
| 2 | Utility of TPP-manufactured biophysical restrictions to probe multiscale cellular dynamics显示文摘Biophysical restrictions regulate protein diffusion,nucleus deformation,and cell migration,which are all universal and important processes for cells to perform their biological functions.However,current technologies addressing these multiscale questions are extremely limited.Herein,through two-photon polymerization(TPP),we present the precise,low-cost,and multiscale microstructures(micro-fences)as a versatile investigating platform.With nanometer-scale printing resolution and multiscale scanning capacity,TPP is capable of generating micro-fences with sizes of 0.5-1000μm.These micro-fences are utilized as biophysical restrictions to determine the fluidity of supported lipid bilayers(SLB),to investigate the restricted diffusion of Src family kinase protein Lck on SLB,and also to reveal the mechanical bending of cell nucleus and T cell climbing ability.Taken together,the proposed versatile and low-cost micro-fences have great potential in probing the restricted dynamics of molecules,organelles,and cells to understand the basics of physical biology. | Panyu Fei Haibo Ding Yu Duan Xinyi Wang Wei Hu Peng Wu Mengxiao Wei Zhengchun Peng Zhongze Gu Wei Chen | 2021 | Bio-Design and Manufacturing2021，4，4： | 0 |
| 3 | 机械力诱导MHC-Ⅰ构象变化增强TCR抗原识别及T细胞活化显示文摘CD8+T细胞主要通过T细胞表面受体(T cell recep tor,TCR)识别并与Ⅰ型主要组织性复合物提呈的抗原(pMHC-Ⅰ)相互作用[1]。TCR对刺激型抗原的识别在CD8+T细胞毒性和适应性免疫中发挥着关键作用。许多证据表明机械力可以延长TCR与刺激性pMHC作用的键合时间(bond lifetime)形成抗原特异性逆锁键(catch bond)[2],并且这种逆锁键对抗原识别非常重要。然而,机械力调控TCR抗原识别的具体结构机制仍不清楚。通过分子动力学模拟、单分子生物膜力学探针、磁镊、T细胞活化实验和动物模型对此问题展开了系统的研究[4]。发现作用在TCR-pMHC-Ⅰ复合体上的拉力可以作用在TCR-pMHC-Ⅰ复合体上的拉力可以打破MHC-I分子内部α1-α2和β2结构域间的相互作用,导致α1-α2结构域旋转并发生构象变化。力诱导的MHC-I构象变化可以进一步别构地调节TCR与刺激性抗原肽及α1-α2结构域的构象及相互作用,诱导产生新的氢键,增强TCR-pMHC-Ⅰ之间的键合时间,但并不能增强TCR与抑制性pMHC-Ⅰ之间的作用。当用点突变阻断这些新形成的氢键,或者α1-α2和β2结构域被二硫键锁住时,最佳力诱导的TCR-pMHC-Ⅰ作用的键合时间明显缩短并且T细胞的活化受到抑制。另外,在人TCR和HLA-A2相互作用中发现了类似机制,并且与肿瘤相关的HLA-A2点突变[3]可以通过限制HLA-A2α1--α2和β2结构域之间的构象打开减弱TCR对肿瘤抗原的识别及T细胞的功能。研究结果表明,机械力诱导的MHC-I构象变化对TCR抗原识别和T细胞活化非常重要,进一步地阐明了机械力调控TCR抗原识别机制,为临床肿瘤的免疫治疗和药物设计提供了新思路和新靶点。 | Peng Wu Tongtong Zhang Baoyu Liu Panyu Fei Lei Cui Rui Qin Huaying Zhu Danmei Yao Ryan Martinez Wei Hu Chenyi An Yong Zhang Junwei Liu Weiwei Yin Jie Sun Chun Zhou Xun Zeng Jianan Wang Brian Evavold Cheng Zhu Jizhong Lou Wei Chen | 2019 | 医用生物力学2019，34，A01： | 0 |
| 4 | Author Correction: Mechanical activation of spike fosters SARS- CoV-2 infection显示文摘 | Wei Hu Yong Zhang Panyu Fei Tongtong Zhang Danmei Yao Yufei Gao Jia Liu Hui Chen Qiao Lu Tenny Mudianto Xinrui Zhang Chuxuan Xiao Yang Ye Qiming Sun Jing Zhang Qi Xie Pei-Hui Wang Jun Wang Zhenhai Li Jizhong Lou Wei Chen | 2021 | Cell Research2021，31，11： | 0 |
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