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000289082 041__ $$aEnglish
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000289082 1001_ $$aZoltsman, Guy$$b0
000289082 245__ $$aA unique chaperoning mechanism in class A JDPs recognizes and stabilizes mutant p53.
000289082 260__ $$aNew York, NY$$bElsevier$$c2024
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000289082 520__ $$aJ-domain proteins (JDPs) constitute a large family of molecular chaperones that bind a broad spectrum of substrates, targeting them to Hsp70, thus determining the specificity of and activating the entire chaperone functional cycle. The malfunction of JDPs is therefore inextricably linked to myriad human disorders. Here, we uncover a unique mechanism by which chaperones recognize misfolded clients, present in human class A JDPs. Through a newly identified β-hairpin site, these chaperones detect changes in protein dynamics at the initial stages of misfolding, prior to exposure of hydrophobic regions or large structural rearrangements. The JDPs then sequester misfolding-prone proteins into large oligomeric assemblies, protecting them from aggregation. Through this mechanism, class A JDPs bind destabilized p53 mutants, preventing clearance of these oncoproteins by Hsp70-mediated degradation, thus promoting cancer progression. Removal of the β-hairpin abrogates this protective activity while minimally affecting other chaperoning functions. This suggests the class A JDP β-hairpin as a highly specific target for cancer therapeutics.
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000289082 650_7 $$2Other$$aJ-domain proteins
000289082 650_7 $$2Other$$aNMR
000289082 650_7 $$2Other$$amolecular chaperones
000289082 650_7 $$2Other$$ap53
000289082 650_7 $$2Other$$aprotein aggregation
000289082 650_7 $$2Other$$aprotein misfolding
000289082 7001_ $$0P:(DE-He78)90f17d2647fa3fc86456473d3ddc6af9$$aDang, Thi Lieu$$b1$$udkfz
000289082 7001_ $$aKuchersky, Miriam$$b2
000289082 7001_ $$aFaust, Ofrah$$b3
000289082 7001_ $$aSilva, Micael S$$b4
000289082 7001_ $$aIlani, Tal$$b5
000289082 7001_ $$aWentink, Anne S$$b6
000289082 7001_ $$0P:(DE-He78)9d539bc25fa8f4ff093b6f6e10d39476$$aBukau, Bernd$$b7$$udkfz
000289082 7001_ $$aRosenzweig, Rina$$b8
000289082 773__ $$0PERI:(DE-600)2001948-8$$a10.1016/j.molcel.2024.02.018$$gp. S1097276524001370$$n8$$p1512-1526.e9$$tMolecular cell$$v84$$x1097-2765$$y2024
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