Hsp70 Inhibits Aggregation of IAPP by Binding to the Heterogeneous Prenucleation Oligomers

Chilukoti, Neeraja; Sil, Timir Baran; Sahoo, Bankanidhi; Deepa, Sathyaseelan S.; Cherakara, Sreelakshmi; Maddheshiya, Mithun; Garai, Kanchan

doi:10.1016/j.bpj.2020.12.019

Cited by 10 publications

(8 citation statements)

References 71 publications

(116 reference statements)

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“…Understanding the structure of these conformers is key to developing therapeutics since fibrillar conformers are linked to late stages of T2DM so being able to prevent or slow fibril formation may prevent onset of the disease. A recent study showed that the molecular chaperone Hsp70 binds to oligomers but not monomers [ 175 ] hence exploiting the use of chaperones as a therapeutic may be useful in the future as it only binds to misfolded forms. It is clear that interactions with membranes are an important factor in the misfolding events so understanding this interaction in more detail could also be an important target for therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Linking hIAPP misfolding and aggregation with type 2 diabetes mellitus: a structural perspective

2022

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There are over 40 identified human disorders that involve certain proteins folding incorrectly, accumulating in the body causing damage to cells and organs and causing disease. Type 2 Diabetes Mellitus (T2DM) is one of these protein misfolding disorders (PMDs) and involves human islet amyloid polypeptide (hIAPP) misfolding and accumulating in parts of the body, primarily in the pancreas, causing damage to islet cells and affecting glucose regulation. In this review, we have summarised our current understanding of what causes hIAPP to misfold, what conformations are found in different parts of the body with a particular focus on what is known about the structure of hIAPP and how this links to T2DM. Understanding the molecular basis behind these misfolding events is essential for understanding the role of hIAPP to develop better therapeutics since type 2 diabetes currently affects over 4.9 million people in the United Kingdom alone and is predicted to increase as our population ages.

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Section: Discussionmentioning

confidence: 99%

Linking hIAPP misfolding and aggregation with type 2 diabetes mellitus: a structural perspective

2022

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“…The data in Figure 7 is restricted to metazoan Hsp70s, however experiments with the bacterial Hsp70 homolog DnaK (net charge −30) suggest that this mechanism also applies. Specifically, DnaK has been reported to bind positively charged IAPP oligomers in the pM-range 35 . However, the affinity of DnaK for oligomers may not be directly comparable to metazoan Hsp70 data in Figure 7, because DnaK can bind monomeric peptides with ten-fold higher affinity than is observed for metazoan Hsp70s (Supplemental Table 2).…”

Section: Discussionmentioning

confidence: 99%

Electrostatics cause the molecular chaperone BiP to preferentially bind oligomerized states of a client protein

Kotler

Wei

Deans

et al. 2021

Preprint

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Hsp70-family 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 Hsp70s differentiate between monomeric and oligomeric states of a target protein. Here we examine the interaction of BiP (the Hsp70 paralog in the endoplasmic reticulum) with proIGF2, the pro-protein form of IGF2 that includes a long and mostly disordered E-peptide region that promotes proIGF2 oligomerization. We discover that electrostatic attraction enables the negatively charged BiP to bind positively charged E-peptide oligomers with low nanomolar affinity. We identify the specific BiP binding sites on proIGF2, and although some are positively charged, as monomers they bind BiP with characteristically low affinity in the micromolar range. We conclude that electrostatics enable BiP to preferentially recognize oligomeric states of proIGF2. Electrostatic targeting of Hsp70 to aggregates may be broadly applicable, as all the currently-documented cases in which Hsp70 binds aggregates with high-affinity involve clients that are expected to be positively charged.

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“…HSP70 was found to be implicated at early steps in the fibrillation process, inhibiting the fibrillation of a multitude of amyloidogenic proteins (Aβ, α-synuclein, Huntingtin, IAPP) ( Muchowski et al, 2000 ; Klucken et al, 2004 ; Evans et al, 2006 ; Monsellier et al, 2014 ; Burmann et al, 2020 ; Chilukoti et al, 2021 ). The majority of studies conclude that HSP70 is interacting with an oligomeric species.…”

Section: Interaction Of Amyloidogenic Proteins With Chaperones and In...mentioning

confidence: 99%

The role of heat shock proteins in preventing amyloid toxicity

Törner

Kupreichyk

Hoyer

et al. 2022

Front. Mol. Biosci.

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The oligomerization of monomeric proteins into large, elongated, β-sheet-rich fibril structures (amyloid), which results in toxicity to impacted cells, is highly correlated to increased age. The concomitant decrease of the quality control system, composed of chaperones, ubiquitin-proteasome system and autophagy-lysosomal pathway, has been shown to play an important role in disease development. In the last years an increasing number of studies has been published which focus on chaperones, modulators of protein conformational states, and their effects on preventing amyloid toxicity. Here, we give a comprehensive overview of the current understanding of chaperones and amyloidogenic proteins and summarize the advances made in elucidating the impact of these two classes of proteins on each other, whilst also highlighting challenges and remaining open questions. The focus of this review is on structural and mechanistic studies and its aim is to bring novices of this field “up to speed” by providing insight into all the relevant processes and presenting seminal structural and functional investigations.

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Hsp70 Inhibits Aggregation of IAPP by Binding to the Heterogeneous Prenucleation Oligomers

Cited by 10 publications

References 71 publications

Linking hIAPP misfolding and aggregation with type 2 diabetes mellitus: a structural perspective

Linking hIAPP misfolding and aggregation with type 2 diabetes mellitus: a structural perspective

Electrostatics cause the molecular chaperone BiP to preferentially bind oligomerized states of a client protein

The role of heat shock proteins in preventing amyloid toxicity

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