<br>人小热休克蛋白 B8 抑制蛋白质聚集而不影响天然折叠过程,Journal of the American Chemical Society

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人小热休克蛋白 B8 抑制蛋白质聚集而不影响天然折叠过程
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-07-06 , DOI: 10.1021/jacs.3c02022
Dhawal Choudhary _{1,

2,

3} , Laura Mediani ₄ , Mario J Avellaneda ₃ , Sveinn Bjarnason ₅ , Simon Alberti ₆ , Edgar E Boczek ₆ , Pétur O Heidarsson ₅ , Alessandro Mossa _{2,

7} , Serena Carra ₄ , Sander J Tans ₃ , Ciro Cecconi _{1,

2}

Affiliation

小热休克蛋白 (sHSP) 是我们蛋白质质量控制系统的关键组成部分，被认为可以充当中和不可逆蛋白质聚集的储存库。然而，sHSP 也可以充当隔离酶，促进蛋白质隔离成聚集体，从而挑战我们对其确切作用机制的理解。在这里，我们利用光镊探索人类小热休克蛋白 HSPB8 及其致病突变体 K141E 的作用机制，该突变体与神经肌肉疾病相关。通过单分子操作实验，我们研究了HSPB8及其K141E突变体如何影响麦芽糖结合蛋白的重折叠和聚集过程。我们的数据表明 HSPB8 选择性抑制蛋白质聚集而不影响天然折叠过程。这种抗聚集机制与之前的模型不同，之前的模型依赖于未折叠的多肽链或部分折叠结构的稳定性，正如其他分子伴侣所报道的那样。相反，HSPB8 似乎选择性地识别并结合在聚集早期形成的聚集物质，防止它们生长成更大的聚集结构。一致的是，K141E 突变专门针对聚集结构的亲和力，而不影响天然折叠，因此削弱了其抗聚集活性。

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Human Small Heat Shock Protein B8 Inhibits Protein Aggregation without Affecting the Native Folding Process

Small Heat Shock Proteins (sHSPs) are key components of our Protein Quality Control system and are thought to act as reservoirs that neutralize irreversible protein aggregation. Yet, sHSPs can also act as sequestrases, promoting protein sequestration into aggregates, thus challenging our understanding of their exact mechanisms of action. Here, we employ optical tweezers to explore the mechanisms of action of the human small heat shock protein HSPB8 and its pathogenic mutant K141E, which is associated with neuromuscular disease. Through single-molecule manipulation experiments, we studied how HSPB8 and its K141E mutant affect the refolding and aggregation processes of the maltose binding protein. Our data show that HSPB8 selectively suppresses protein aggregation without affecting the native folding process. This anti-aggregation mechanism is distinct from previous models that rely on the stabilization of unfolded polypeptide chains or partially folded structures, as has been reported for other chaperones. Rather, it appears that HSPB8 selectively recognizes and binds to aggregated species formed at the early stages of aggregation, preventing them from growing into larger aggregated structures. Consistently, the K141E mutation specifically targets the affinity for aggregated structures without impacting native folding, and hence impairs its anti-aggregation activity.

更新日期：2023-07-06

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