AlphaFold predicted structure of the Hsp90-like domains of the neurodegeneration linked protein sacsin reveals key residues for ATPase activity.
AlphaFold predicted structure of the Hsp90-like domains of the neurodegeneration linked protein sacsin reveals key residues for ATPase activity.
复制标题
Alphafold预测神经变性蛋白囊蛋白的HSP90样结构域揭示了ATPase活性的关键残基。
DOI：
10.3389/fmolb.2022.1074714
复制
发表时间：
2022
影响因子：
5
通讯作者：
中科院分区：
文献类型：
--
作者：
共济失调相关蛋白sacsin有三个区域的部分同源性热休克蛋白90的N-末端ATP结合域。虽然已经报道了这种Hsp90样结构域的晶体结构，但ATP结合和水解所需的精确分子相互作用尚不清楚，并且ATP结合是否与这些结构域相容是有争议的。此外，与Hsp90的中间结构域等同的sacsin结构域的鉴定一直难以捉摸。在这里，我们提出了与酵母Hsp90，这提供了新的见解sacsin的结构的sacsin的AlphaFold结构的叠加。我们鉴定了囊蛋白Hsp90样结构域中ATP结合和水解所需的残基，包括与Hsp90中间结构域等效的推定催化精氨酸残基。重要的是，我们的分析允许比较的热休克蛋白90的中间结构域与相应的囊蛋白区域，并确定一个较短的盖子部分，在囊蛋白ATP结合结构域，比一个发现在N-末端结构域的热休克蛋白90。我们的研究结果表明，参与ATP结合的囊蛋白的盖子部分的残基的重新排列可以更好地匹配在热休克蛋白90中看到的等效残基，然后我们使用分子动力学模拟证实。我们推测，从结构的角度来看，为什么一些ATP竞争性抑制剂的Hsp90可能不结合sacsin，而其他人会。总之，我们的分析支持了这一假设，即囊蛋白的功能是ATP驱动的，并将与它作为一个超分子伴侣的作用是一致的。我们建议将sacsin的SR 1区域重新命名为HSP-NRD（Hsp90 N-末端重复结构域;残基84 - 324），并将紧接其后的片段重新命名为HSP-MRD（Hsp90中间重复结构域;残基325 - 518）。
The ataxia-linked protein sacsin has three regions of partial homology to Hsp90’s N-terminal ATP binding domain. Although a crystal structure for this Hsp90-like domain has been reported the precise molecular interactions required for ATP-binding and hydrolysis are unclear and it is debatable whether ATP biding is compatible with these domains. Furthermore, the Identification of a sacsin domain(s) equivalent to the middle domain of Hsp90 has been elusive. Here we present the superimposition of an AlphaFold structure of sacsin with yeast Hsp90, which provides novel insights into sacsin’s structure. We identify residues within the sacsin Hsp90-like domains that are required for ATP binding and hydrolysis, including the putative catalytic arginine residues equivalent to that of the Hsp90 middle domain. Importantly, our analysis allows comparison of the Hsp90 middle domain with corresponding sacsin regions and identifies a shorter lid segment, in the sacsin ATP-binding domains, than the one found in the N-terminal domain of Hsp90. Our results show how a realignment of residues in the lid segment of sacsin that are involved in ATP binding can better match equivalent residues seen in Hsp90, which we then corroborated using molecular dynamic simulations. We speculate, from a structural viewpoint, why some ATP competitive inhibitors of Hsp90 may not bind sacsin, while others would. Together our analysis supports the hypothesis that sacsin’s function is ATP-driven and would be consistent with it having a role as a super molecular chaperone. We propose that the SR1 regions of sacsin be renamed as HSP-NRD (Hsp90 N-Terminal Repeat Domain; residues 84-324) and the fragment immediately after as HSP-MRD (Hsp90 Middle Repeat Domain; residues 325-518).
登录
查看更多内容
影响因子：
3.5
作者：
Duncan EJ;Larivière R;Bradshaw TY;Longo F;Sgarioto N;Hayes MJ;Romano LEL;Nethisinghe S;Giunti P;Bruntraeger MB;Durham HD;Brais B;Maltecca F;Gentil BJ;Chapple JP
通讯作者：
Chapple JP
影响因子：
3.5
作者：
Parfitt DA;Michael GJ;Vermeulen EG;Prodromou NV;Webb TR;Gallo JM;Cheetham ME;Nicoll WS;Blatch GL;Chapple JP
通讯作者：
Chapple JP
影响因子：
4.6
作者：
Armstrong HK;Gillis JL;Johnson IRD;Nassar ZD;Moldovan M;Levrier C;Sadowski MC;Chin MY;Tomlinson Guns ES;Tarulli G;Lynn DJ;Brooks DA;Selth LA;Centenera MM;Butler LM
通讯作者：
Butler LM
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：
3.9
作者：
Romano, Alessandro;Tessa, Alessandra;Barca, Amilcare;Fattori, Fabiana;de Leva, Maria Fulvia;Terracciano, Alessandra;Storelli, Carlo;Santorelli, Filippo Maria;Verri, Tiziano
通讯作者：
Verri, Tiziano