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Polyubiquitination by HECT E3s and the determinants of chain type specificity.

ABSTRACT: Polyubiquitination can mediate several different biochemical functions, determined in part by which lysine of ubiquitin is used to link the polyubiquitin chain. Among the HECT domain ubiquitin ligases, some, such as human E6AP, preferentially catalyze the formation of K48-linked polyubiquitin chains, while others, including Saccharomyces cerevisiae Rsp5 and human Itch, preferentially catalyze the formation of K63-linked chains. The features of HECT E3s that determine their chain type specificities have not been identified. We show here that chain type specificity is a function solely of the Rsp5 HECT domain, that the identity of the cooperating E2 protein does not influence the chain type specificity, that single chains produced by Rsp5 contain between 12 and 30 ubiquitin moieties, and that the determinants of chain type specificity are located within the last 60 amino acids of the C lobe of the HECT domain. Our results are also consistent with a simple sequential-addition mechanism for polyubiquitination by Rsp5, rather than a mechanism involving the formation of either E2- or E3-linked polyubiquitin chain transfers.

SUBMITTER: Kim HC

PROVIDER: S-EPMC2698738 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Polyubiquitination by HECT E3s and the determinants of chain type specificity.

Kim Hyung Cheol HC Huibregtse Jon M JM

Molecular and cellular biology 20090413 12

Polyubiquitination can mediate several different biochemical functions, determined in part by which lysine of ubiquitin is used to link the polyubiquitin chain. Among the HECT domain ubiquitin ligases, some, such as human E6AP, preferentially catalyze the formation of K48-linked polyubiquitin chains, while others, including Saccharomyces cerevisiae Rsp5 and human Itch, preferentially catalyze the formation of K63-linked chains. The features of HECT E3s that determine their chain type specificiti ...[more]

PMID: 19364824

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Project description:The Type I Interferon family of cytokines all act through the same cell surface receptor and induce phosphorylation of the same subset of response regulators of the STAT family. Despite their shared receptor, different Type I Interferons have different functions during immune response to infection. In particular, they differ in the potency of their induced anti-viral and anti-proliferative responses in target cells. It remains not fully understood how these functional differences can arise in a ligand-specific manner both at the level of STAT phosphorylation and the downstream function. We use a minimal computational model of Type I Interferon signaling, focusing on Interferon-α and Interferon-β. We validate the model with quantitative experimental data to identify the key determinants of specificity and functional plasticity in Type I Interferon signaling. We investigate different mechanisms of signal discrimination, and how multiple system components such as binding affinity, receptor expression levels and their variability, receptor internalization, short-term negative feedback by SOCS1 protein, and differential receptor expression play together to ensure ligand specificity on the level of STAT phosphorylation. Based on these results, we propose phenomenological functional mappings from STAT activation to downstream anti-viral and anti-proliferative activity to investigate differential signal processing steps downstream of STAT phosphorylation. We find that the negative feedback by the protein USP18, which enhances differences in signaling between Interferons via ligand-dependent refractoriness, can give rise to functional plasticity in Interferon-α and Interferon-β signaling, and explore other factors that control functional plasticity. Beyond Type I Interferon signaling, our results have a broad applicability to questions of signaling specificity and functional plasticity in signaling systems with multiple ligands acting through a bottleneck of a small number of shared receptors.

Dataset Information

Polyubiquitination by HECT E3s and the determinants of chain type specificity.

Publications

Polyubiquitination by HECT E3s and the determinants of chain type specificity.

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