De novo design of monomeric helical bundles for pH-controlled membrane lysis.
De novo design of monomeric helical bundles for pH-controlled membrane lysis.
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DOI：
10.1002/pro.4769
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发表时间：
2023-11
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影响因子：
--
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通过受体介导的内吞作用进行靶向细胞内递送需要递送的货物逸出内体以防止溶酶体降解。原则上，这可以通过在内化时紧密限制于内体膜的膜裂解来实现，以避免一般的膜插入和裂解。在这里，我们描述了带有埋藏组氨酸的小单体蛋白的设计，其中包含 pH 响应氢键网络和膜渗透两亲螺旋。在经过实验测试的 30 种设计中，全部在大肠杆菌中表达，其中 13 种是具有预期二级结构的单体，4 种设计以 pH 依赖性方式破坏人工脂质体。突变分析表明，埋藏的组氨酸氢键网络介导 pH 响应性，并在非常窄的 pH 范围（6.0-5.5）内控制模型膜的裂解，而在中性 pH 下几乎不发生裂解。这些严格控制的裂解单体可以帮助介导设计的靶向递送平台中的内体逃逸。
Targeted intracellular delivery via receptor‐mediated endocytosis requires the delivered cargo to escape the endosome to prevent lysosomal degradation. This can in principle be achieved by membrane lysis tightly restricted to endosomal membranes upon internalization to avoid general membrane insertion and lysis. Here, we describe the design of small monomeric proteins with buried histidine containing pH‐responsive hydrogen bond networks and membrane permeating amphipathic helices. Of the 30 designs that were experimentally tested, all expressed in Escherichia coli, 13 were monomeric with the expected secondary structure, and 4 designs disrupted artificial liposomes in a pH‐dependent manner. Mutational analysis showed that the buried histidine hydrogen bond networks mediate pH‐responsiveness and control lysis of model membranes within a very narrow range of pH (6.0–5.5) with almost no lysis occurring at neutral pH. These tightly controlled lytic monomers could help mediate endosomal escape in designed targeted delivery platforms.
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影响因子：
5.6
作者：
Grigoryan G;Degrado WF
通讯作者：
Degrado WF
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
64.8
作者：
Bhardwaj, Gaurav;Mulligan, Vikram Khipple;Bahl, Christopher D.;Gilmore, Jason M.;Harvey, Peta J.;Cheneval, Olivier;Buchko, Garry W.;Pulavarti, Surya V. S. R. K.;Kaas, Quentin;Eletsky, Alexander;Huang, Po-Ssu;Johnsen, William A.;Greisen, Per Jr;Rocklin, Gabriel J.;Song, Yifan;Linsky, Thomas W.;Watkins, Andrew;Rettie, Stephen A.;Xu, Xianzhong;Carter, Lauren P.;Bonneau, Richard;Olson, James M.;Coutsias, Evangelos;Correnti, Colin E.;Szyperski, Thomas;Craik, David J.;Baker, David
通讯作者：
Baker, David
影响因子：
2.9
作者：
BLUMENTHAL, R;SETH, P;PASTAN, I
通讯作者：
PASTAN, I
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K