Release of a disordered domain enhances HspB1 chaperone activity toward tau

Abstract

Small heat shock proteins (sHSPs) are a class of ATP-independent molecular chaperones that play vital roles in maintaining protein solubility and preventing aberrant protein aggregation. They form highly dynamic, polydisperse oligomeric ensembles and contain long intrinsically disordered regions. Experimental challenges posed by these properties have greatly impeded our understanding of sHSP structure and mechanism of action. Here we characterize interactions between the human sHSP HspB1 (Hsp27) and microtubule-associated protein tau, which is implicated in multiple dementias, including Alzheimer’s disease. We show that tau binds both to a well-known binding groove within the structured alpha-crystallin domain (ACD) and to sites within the enigmatic, disordered N-terminal region (NTR) of HspB1. However, only interactions involving the NTR lead to productive chaperone activity, whereas ACD binding is uncorrelated with chaperone function. The tau-binding groove in the ACD also binds short hydrophobic regions within HspB1 itself, and HspB1 mutations that disrupt these intrinsic ACD–NTR interactions greatly enhance chaperone activity toward tau. This leads to a mechanism in which the release of the disordered NTR from a binding groove on the ACD enhances chaperone activity toward tau. The study advances understanding of the mechanisms by which sHSPs achieve their chaperone activity against amyloid-forming clients and how cells defend against pathological tau aggregation. Furthermore, the resulting mechanistic model points to ways in which sHSP chaperone activity may be increased, either by native factors within the cell or by therapeutic intervention.

A weakened interface in the P182L variant of HSP27 associated with severe Charcot‐Marie‐Tooth neuropathy causes aberrant binding to interacting proteins

“…Therefore, increased availability of the β4/β8 groove in P182L IxI/V would leave its β4/β8 groove more accessible to interactions with other inter‐ and intramolecular contacts and could reduce the number of NTD‐substrate interactions and decrease the overall chaperone activity of the HSP27 chaperone. At least for the substrate tau, it was shown that the NTD is required to prevent substrate aggregation, whereas binding of tau to the β4/β8 groove does not prevent substrate aggregation (Baughman et al, 2020).…”

Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies

“…Interestingly, these two chaperones are predicted to affect tau aggregation through different but complementary mechanisms. While HSPB1 is considered a “first responder” to delay formation of toxic oligomers [ 219 ], HSC70 interacts with oligomers and later species in the fibril formation pathway to protect from toxic conformations and promote degradation [ 218 ]. Meanwhile, the chaperone HSP90 has been proposed to promote tau proteasomal degradation through unclear mechanisms [ 220 ].…”

A Disorder-to-Order Transition Activates an ATP-Independent Membrane Protein Chaperone

“…For example, small heat shock proteins deoligomerize and become partially disordered upon heat stress, which activates them to prevent misfolded proteins from aggregation. 4 , 7 , 64 – 66 Other stresses, such as acidic pH or oxidation, trigger unfolding transitions that activate chaperones such as HdeA, Hsp33, and Hsp26. 5 , 6 , 67 , 68 Our work shows that the opposite transition is used to activate cpSRP43, analogous to the Spy 13 and Skp 11 chaperones that protect nascent membrane proteins during their transit across the bacterial periplasm.…”

“… 1 – 3 Many ATP-independent small heat shock proteins undergo changes in oligomeric state and/or unfolding transitions upon activation under stress conditions. 4 – 7 …”