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Subverting Hedgehog Protein Autoprocessing by Chemical Induction of Paracatalysis.

ABSTRACT: Hedgehog proteins, a family of vital cell signaling factors, are expressed in precursor form, which requires specialized autoprocessing, called cholesterolysis, for full biological activity. Cholesterolysis occurs in cis through the action of the precursor's C-terminal enzymatic domain, HhC. In this work, we describe HhC activator compounds (HACs), a novel class of noncovalent modulators that induce autoprocessing infidelity, diminishing native cholesterolysis in favor of precursor autoproteolysis, an otherwise minor and apparently nonphysiological side reaction. HAC-induced autoproteolysis generates hedgehog protein that is cholesterol free and hence signaling deficient. The most effective HAC has an AC₅₀ of 9 ?M, accelerates HhC autoproteolytic activity by 225-fold, and functions in the presence and absence of cholesterol, the native substrate. HACs join a rare class of "antagonists" that suppress native enzymatic activity by subverting mechanistic fidelity.

SUBMITTER: Smith CJ

PROVIDER: S-EPMC7031038 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Subverting Hedgehog Protein Autoprocessing by Chemical Induction of Paracatalysis.

Smith Carl J CJ Wagner Andrew G AG Stagnitta Robert T RT Xu Zihan Z Pezzullo John L JL Giner José-Luis JL Xie Jian J Covey Douglas F DF Wang Chunyu C Callahan Brian P BP

Biochemistry 20200204 6

Hedgehog proteins, a family of vital cell signaling factors, are expressed in precursor form, which requires specialized autoprocessing, called cholesterolysis, for full biological activity. Cholesterolysis occurs <i>in cis</i> through the action of the precursor's C-terminal enzymatic domain, HhC. In this work, we describe HhC activator compounds (HACs), a novel class of noncovalent modulators that induce autoprocessing infidelity, diminishing native cholesterolysis in favor of precursor autopr ...[more]

PMID: 32013401

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Project description:Dual targeting is a relatively little explored phenomenon by which some proteins are transported to two different subcellular compartments, such as chloroplasts and mitochondria. We previously showed that the R domain and the arm region of the melon necrotic spot virus coat protein could act as a dual-targeting peptide, which shares many relevant features in structure, amino acid composition, and functionality with that of the Thr-tRNA synthetases, the best-studied dual-targeted proteins by far. Here, we show that a viral coat protein hijacks the general pathways for organellar protein import and identifies the coat protein-interacting organellar translocon receptors. Our findings demonstrate for the first time that an exogenous dual-targeted protein uses the general Toc and Tom import systems to reach mitochondria and chloroplasts because it depends on the availability of NbToc75 and NbTom40. Interaction studies, subcellular localization analysis, and viral infection assays in silenced plants revealed the significance of plant receptors, such as the mitochondrion NbOm64 and chloroplast NbToc159A, in this transport. We also show that chloroplast protein translocation impairment could be interlinked with retrograde communication triggering a JA-based response that incidentally impairs viral infection. Future research may profit from our results to better comprehend cellular communication, protein import mechanisms, how preproteins interact with their receptors, and how plant pathogens manipulate host machinery to their ends. IMPORTANCE Many plant proteins and some proteins from plant pathogens are dually targeted to chloroplasts and mitochondria, and are supposed to be transported along the general pathways for organellar protein import, but this issue has not been explored yet. Moreover, organellar translocon receptors exist as families of several members whose functional specialization in different cargos is supposed but not thoroughly studied. This article provides novel insights into such topics showing for the first time that an exogenous protein, the melon necrotic spot virus coat protein, exploits the common Toc/Tom import systems to enter both mitochondria and chloroplasts while identifying the involved specific receptors.

Dataset Information

Subverting Hedgehog Protein Autoprocessing by Chemical Induction of Paracatalysis.

Publications

Subverting Hedgehog Protein Autoprocessing by Chemical Induction of Paracatalysis.

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