Probing the biophysical constraints of SARS-CoV-2 spike N-terminal domain using deep mutational scanning.
Probing the biophysical constraints of SARS-CoV-2 spike N-terminal domain using deep mutational scanning.
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DOI：
10.1126/sciadv.add7221
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发表时间：
2022-11-25
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
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作者：
提高 SARS-CoV-2 刺突 (S) 蛋白的表达水平对于 COVID-19 疫苗的开发至关重要。虽然之前的努力主要集中在改造受体结合结构域 (RBD) 和 S2 亚基，但氨基末端结构域 (NTD) 由于对其生物物理限制的了解有限而长期被忽视。在这项研究中，通过深度突变扫描量化了数千个 NTD 单突变对 S 蛋白表达的影响。我们的结果表明，就 S 蛋白表达而言，NTD 残基的突变耐受性与其与 RBD 和 S2 的接近程度呈负相关。我们还在域间界面处发现了 NTD 突变，该突变增加了 S 蛋白的表达而不改变其抗原性。总的来说，这项研究不仅增进了对 NTD 生物物理限制的理解，而且还为基于 S 的免疫原设计提供了宝贵的见解。对数千个 SARS-CoV-2 S 蛋白 NTD 突变的调查揭示了免疫原优化的补充策略。
Increasing the expression level of the SARS-CoV-2 spike (S) protein has been critical for COVID-19 vaccine development. While previous efforts largely focused on engineering the receptor-binding domain (RBD) and the S2 subunit, the amino-terminal domain (NTD) has been long overlooked because of the limited understanding of its biophysical constraints. In this study, the effects of thousands of NTD single mutations on S protein expression were quantified by deep mutational scanning. Our results revealed that in terms of S protein expression, the mutational tolerability of NTD residues was inversely correlated with their proximity to the RBD and S2. We also identified NTD mutations at the interdomain interface that increased S protein expression without altering its antigenicity. Overall, this study not only advances the understanding of the biophysical constraints of the NTD but also provides invaluable insights into S-based immunogen design. A survey on thousands of SARS-CoV-2 S protein NTD mutations reveals a complementary strategy for immunogen optimization.
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影响因子：
16.6
作者：
Greaney AJ;Starr TN;Barnes CO;Weisblum Y;Schmidt F;Caskey M;Gaebler C;Cho A;Agudelo M;Finkin S;Wang Z;Poston D;Muecksch F;Hatziioannou T;Bieniasz PD;Robbiani DF;Nussenzweig MC;Bjorkman PJ;Bloom JD
通讯作者：
Bloom JD
影响因子：
16.6
作者：
通讯作者：
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改进的荧光蛋白用于内源性蛋白质标记。
影响因子：
16.6
作者：
Feng S;Sekine S;Pessino V;Li H;Leonetti MD;Huang B
通讯作者：
Huang B
DOI：
10.1056/nejmoa2107659
发表时间：
2021-09-23
期刊：
The New England journal of medicine
影响因子：
--
作者：
Heath PT;Galiza EP;Baxter DN;Boffito M;Browne D;Burns F;Chadwick DR;Clark R;Cosgrove C;Galloway J;Goodman AL;Heer A;Higham A;Iyengar S;Jamal A;Jeanes C;Kalra PA;Kyriakidou C;McAuley DF;Meyrick A;Minassian AM;Minton J;Moore P;Munsoor I;Nicholls H;Osanlou O;Packham J;Pretswell CH;San Francisco Ramos A;Saralaya D;Sheridan RP;Smith R;Soiza RL;Swift PA;Thomson EC;Turner J;Viljoen ME;Albert G;Cho I;Dubovsky F;Glenn G;Rivers J;Robertson A;Smith K;Toback S;2019nCoV-302 Study Group
通讯作者：
2019nCoV-302 Study Group
影响因子：
48
作者：
Fowler, Douglas M.;Fields, Stanley
通讯作者：
Fields, Stanley