6nsv
Crystal structure of the human CHIP TPR domain in complex with a 5mer acetylated optimized peptideCrystal structure of the human CHIP TPR domain in complex with a 5mer acetylated optimized peptide
Structural highlights
Publication Abstract from PubMedProtein-protein interactions between E3 ubiquitin ligases and protein termini help shape the proteome. These interactions are sensitive to proteolysis, which alters the ensemble of cellular N and C termini. Here we describe a mechanism wherein caspase activity reveals latent C termini that are then recognized by the E3 ubiquitin ligase CHIP. Using expanded knowledge of CHIP's binding specificity, we predicted hundreds of putative interactions arising from caspase activity. Subsequent validation experiments confirmed that CHIP binds the latent C termini at tau(D421) and caspase-6(D179). CHIP binding to tau(D421), but not tau(FL), promoted its ubiquitination, while binding to caspase-6(D179) mediated ubiquitin-independent inhibition. Given that caspase activity generates tau(D421) in Alzheimer's disease (AD), these results suggested a concise model for CHIP regulation of tau homeostasis. Indeed, we find that loss of CHIP expression in AD coincides with the accumulation of tau(D421) and caspase-6(D179). These results illustrate an unanticipated link between caspases and protein homeostasis. Specificity for latent C termini links the E3 ubiquitin ligase CHIP to caspases.,Ravalin M, Theofilas P, Basu K, Opoku-Nsiah KA, Assimon VA, Medina-Cleghorn D, Chen YF, Bohn MF, Arkin M, Grinberg LT, Craik CS, Gestwicki JE Nat Chem Biol. 2019 Aug;15(8):786-794. doi: 10.1038/s41589-019-0322-6. Epub 2019 , Jul 18. PMID:31320752[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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