Terminal Regions Confer Plasticity to the Tetrameric Assembly of Human HspB2 and HspB3.
Terminal Regions Confer Plasticity to the Tetrameric Assembly of Human HspB2 and HspB3.
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DOI：
10.1016/j.jmb.2018.06.047
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发表时间：
2018-09-14
影响因子：
5.6
通讯作者：
Slingsby C
中科院分区：
文献类型：
--
作者：
Clark AR;Vree Egberts W;Kondrat FDL;Hilton GR;Ray NJ;Cole AR;Carver JA;Benesch JLP;Keep NH;Boelens WC;Slingsby C
在小的热休克蛋白（sHsps）的异质结跨越多个时空的制度，从快速波动的蛋白质的一部分，三级结构的构象变化，可塑性的接口，和多分散性的相互转换，并共同组装寡聚体。sHsps的这种异质性和动态性质显著阻碍了它们的结构表征。脊椎动物sHsps特别缺乏原子坐标，其中大多数可用的结构是广泛截断的同源异构体。sHsps在维持细胞中的蛋白质水平方面起重要作用，因此在生物体健康和疾病中起重要作用。HspB 2和HspB 3是脊椎动物sHsps，发现它们在神经肌肉细胞中共组装，其变体与疾病相关。在这里，我们提出了人HspB 2/B3的结构，它以3：1的比例结晶为异源四聚体。在HspB 2/B3四聚体中，四个α-晶体蛋白结构域（ACD）组装成一个扁平的四面体，四面体被两个不相交的近似二联体穿透。组装是由柔性的“螺母和螺栓”介导的，涉及来自填充ACD口袋的末端区域的IXI/V基序。部分N-末端区域以未折叠构象结合到反平行共享ACD二聚体凹槽中。终端区域的轨道没有解决，最有可能是由于它们在晶格中的无序。这第一个结构的全长人类sHsp异聚体揭示了终端区域的异质性相互作用，并建议的可塑性，是重要的sHsps的细胞保护功能。异聚体sHsps的动态行为阻碍了细胞保护的结构生物学。将3：1比例的全长人HspB 2/B3结晶并以3.9-nm分辨率溶解。组装是通过灵活的“螺母和螺栓”从终端区域填充域袋。N-末端区域以未折叠构象结合到共享的二聚体凹槽中。来自非结构化蛋白的IXI/V基序可以在疾病期间被sHsps隔离。
Heterogeneity in small heat shock proteins (sHsps) spans multiple spatiotemporal regimes—from fast fluctuations of part of the protein, to conformational variability of tertiary structure, plasticity of the interfaces, and polydispersity of the inter-converting, and co-assembling oligomers. This heterogeneity and dynamic nature of sHsps has significantly hindered their structural characterization. Atomic coordinates are particularly lacking for vertebrate sHsps, where most available structures are of extensively truncated homomers. sHsps play important roles in maintaining protein levels in the cell and therefore in organismal health and disease. HspB2 and HspB3 are vertebrate sHsps that are found co-assembled in neuromuscular cells, and variants thereof are associated with disease. Here, we present the structure of human HspB2/B3, which crystallized as a hetero-tetramer in a 3:1 ratio. In the HspB2/B3 tetramer, the four α-crystallin domains (ACDs) assemble into a flattened tetrahedron which is pierced by two non-intersecting approximate dyads. Assembly is mediated by flexible “nuts and bolts” involving IXI/V motifs from terminal regions filling ACD pockets. Parts of the N-terminal region bind in an unfolded conformation into the anti-parallel shared ACD dimer grooves. Tracts of the terminal regions are not resolved, most likely due to their disorder in the crystal lattice. This first structure of a full-length human sHsp heteromer reveals the heterogeneous interactions of the terminal regions and suggests a plasticity that is important for the cytoprotective functions of sHsps. Dynamic behavior of heteromeric sHsps hinders structural biology of cytoprotection. Full-length human HspB2/B3 in 3:1 ratio was crystallized and solved at 3.9-Å resolution. Assembly is by flexible “nuts and bolts” from terminal regions filling domain pockets. N-terminal regions bind in an unfolded conformation into shared dimer grooves. IXI/V motifs from unstructured proteins may be sequestered by sHsps during disease.
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影响因子：
3.7
作者：
Heirbaut M;Beelen S;Strelkov SV;Weeks SD
通讯作者：
Weeks SD
DOI：
10.1098/rstb.2011.0405
发表时间：
2013-05-05
期刊：
Philosophical transactions of the Royal Society of London. Series B, Biological sciences
影响因子：
--
作者：
Hilton GR;Hochberg GK;Laganowsky A;McGinnigle SI;Baldwin AJ;Benesch JL
通讯作者：
Benesch JL
影响因子：
4.8
作者：
Heirbaut, Michelle;Lermyte, Frederik;Weeks, Stephen D.
通讯作者：
Weeks, Stephen D.
影响因子：
5.7
作者：
Hanazono, Yuya;Takeda, Kazuki;Miki, Kunio
通讯作者：
Miki, Kunio
DOI：
10.1016/s0141-8130(98)00013-0
发表时间：
1998-05-01
影响因子：
8.2
作者：
de Jong, WW;Caspers, GJ;Leunissen, JAM
通讯作者：
Leunissen, JAM