Electrostatics Drive the Molecular Chaperone BiP to Preferentially Bind Oligomerized States of a Client Protein.
Electrostatics Drive the Molecular Chaperone BiP to Preferentially Bind Oligomerized States of a Client Protein.
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静电驱动分子伴侣BIP以优先结合客户蛋白的寡聚状态。
DOI：
10.1016/j.jmb.2022.167638
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发表时间：
2022-07-15
影响因子：
5.6
通讯作者：
Street, Timothy O.
中科院分区：
文献类型：
--
作者：
Deans, Erin E.;Kotler, Judy L. M.;Wei, Wei-Shao;Street, Timothy O.
Hsp 70分子伴侣在低微摩尔范围内以弱特征亲和力结合短单体肽，但也可以以低纳摩尔亲和力结合一些聚集体、原纤维和淀粉样蛋白。虽然这种差异亲和力使Hsp 70能够优先靶向潜在的毒性聚集体，但尚不清楚伴侣蛋白如何区分客户蛋白的单体和聚集状态，以及为什么仅观察到某些聚集客户而不是其他客户的优先结合。在这里，我们研究了BiP（内质网中的Hsp 70蛋白）与客户端proIGF 2的相互作用，proIGF 2是IGF 2的前蛋白形式，包括一个长而大部分无序的E肽区域，促进proIGF 2寡聚化。通过剖析BiP靶向proIGF 2和E肽寡聚体的机制，我们发现静电吸引是寡聚体识别的强大驱动力。我们确定了proIGF 2上的特定BiP结合位点，并且作为单体，它们在低微摩尔范围内以特征性的弱亲和力结合BiP，但是对E-肽寡聚体的静电吸引将亲和力提高到低纳摩尔水平。静电的主导作用在动力学上表现为转向力，其加速BiP与E-肽寡聚体的结合，与单体肽相比，其结合大约两个数量级。Hsp 70的静电靶向提供了一个解释，为什么优先结合已被观察到一些聚集的客户端，而不是其他人，因为所有目前记录的情况下，其中Hsp 70结合聚集体与高亲和力涉及客户端，具有相反的电荷Hsp 70。
Hsp70 chaperones bind short monomeric peptides with a weak characteristic affinity in the low micromolar range, but can also bind some aggregates, fibrils, and amyloids, with low nanomolar affinity. While this differential affinity enables Hsp70 to preferentially target potentially toxic aggregates, it is unknown how a chaperone can differentiate between monomeric and aggregated states of a client protein and why preferential binding is only observed for some aggregated clients but not others. Here we examine the interaction of BiP (the Hsp70 paralog in the endoplasmic reticulum) with the client proIGF2, the pro-protein form of IGF2 that includes a long and mostly disordered E-peptide region that promotes proIGF2 oligomerization. By dissecting the mechanism by which BiP targets proIGF2 and E-peptide oligomers we discover that electrostatic attraction is a powerful driving force for oligomer recognition. We identify the specific BiP binding sites on proIGF2 and as monomers they bind BiP with characteristically weak affinity in the low micromolar range, but electrostatic attraction to E-peptide oligomers boosts the affinity to the low nanomolar level. The dominant role of electrostatics is manifested kinetically as a steering force that accelerates the binding of BiP to E-peptide oligomers by approximately two orders of magnitude as compared against monomeric peptides. Electrostatic targeting of Hsp70 provides an explanation for why preferential binding has been observed for some aggregated clients but not others, as all the currently-documented cases in which Hsp70 binds aggregates with high-affinity involve clients that have an opposite charge to Hsp70.
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DOI：
10.1126/science.1173155
发表时间：
2009-07-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Maji SK;Perrin MH;Sawaya MR;Jessberger S;Vadodaria K;Rissman RA;Singru PS;Nilsson KP;Simon R;Schubert D;Eisenberg D;Rivier J;Sawchenko P;Vale W;Riek R
通讯作者：
Riek R
影响因子：
11.4
作者：
Gamer, J;Multhaup, G;Bukau, B
通讯作者：
Bukau, B
影响因子：
16
作者：
Feige, Matthias J.;Groscurth, Sandra;Marcinowski, Moritz;Shimizu, Yuichiro;Kessler, Horst;Hendershot, Linda M.;Buchner, Johannes
通讯作者：
Buchner, Johannes
DOI：
10.1073/pnas.0903503106
发表时间：
2009-05-26
影响因子：
11.1
作者：
Bertelsen, Eric B.;Chang, Lyra;Zuiderweg, Erik R. P.
通讯作者：
Zuiderweg, Erik R. P.
影响因子：
4.8
作者：
Duguay, SJ;Jin, Y;Steiner, DF
通讯作者：
Steiner, DF