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Targeting protein‐protein interactions in chaperone complexes to normalize proteostasis
Author(s) -
Gestwicki Jason E.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.247.1
Subject(s) - proteostasis , chaperone (clinical) , co chaperone , protein folding , chaperonin , chemical chaperone , computational biology , small molecule , protein aggregation , drug discovery , protein–protein interaction , chemistry , hsp90 , biology , microbiology and biotechnology , bioinformatics , biochemistry , heat shock protein , unfolded protein response , endoplasmic reticulum , medicine , gene , pathology
The ~300 molecular chaperones in mammals are thought to work together to maintain protein homeostasis (proteostasis). Often, this process is carried out by groups of chaperones that physically interact with each other and with their client proteins. Thus, chaperones can be thought of as a network that is held together by either stable or transient protein‐protein interactions (PPIs). This chaperone network protects unfolded clients and shepards them through folding, function and turnover. Our goal is to understand the logic of chaperone‐mediated protein quality control decisions. Our approach is to: (a) study the PPIs between chaperones and clients and (b) create drug‐like small molecules that perturb these PPIs. In turn, we can use these molecules to probe the role of specific PPIs in quality control. Towards this goal, we have mapped the interactions of a model client, tau, with chaperone subnetworks and identified chaperones that bind directly to this client. Interestingly, we found that a subset of these chaperones had strong anti‐aggregation and anti‐prion activity. Leveraging this knowledge, we created high throughput screening (HTS) platforms to activate the specific anti‐aggregation sub‐network. Following a medicinal chemistry campaign, the lead molecules promoted turnover of tau in multiple disease models, consistent with the model. Together, these ongoing studies have illuminated the logic of protein quality control and provided a set of chemical tools for addressing chaperone function in other systems. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .