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"Mallostery"-ligand-dependent protein misfolding enables physiological regulation by ERAD.

ABSTRACT: HMG-CoA reductase (HMGR) undergoes regulated degradation as part of feedback control of the sterol pathway. In yeast, the stability of the HMGR isozyme Hmg2 is controlled by the 20-carbon isoprenoid geranylgeranyl pyrophosphate (GGPP). Increasing GGPP levels cause more efficient degradation by the HMG-CoA reductase degradation (HRD) pathway, allowing for feedback regulation of HMGR. The HRD pathway is critical for the endoplasmic reticulum (ER)-associated degradation (ERAD) of misfolded ER proteins. Here, we have explored GGPP's role in HRD-dependent Hmg2 degradation. We found that GGPP potently regulates Hmg2 levels in vivo and causes reversible Hmg2 misfolding at nanomolar concentrations in vitro These GGPP-mediated effects were absent in several stabilized or nonregulated Hmg2 mutants. Consistent with its high potency, GGPP's effects were highly specific such that other structurally related molecules were ineffective in altering Hmg2 structure. For instance, two closely related GGPP analogues, 2F-GGPP and GGSPP, were completely inactive at all concentrations tested. Furthermore, GGSPP antagonized GGPP's effects in vivo and in vitro Chemical chaperones reversed GGPP's effects on Hmg2 structure and degradation, suggesting that GGPP causes selective Hmg2 misfolding. These results indicate that GGPP functions in a manner similar to an allosteric ligand, causing Hmg2 misfolding through interaction with a reversible, specific binding site. Consistent with this, the Hmg2 protein formed multimers, typical of allosteric proteins. We propose that this "allosteric misfolding," or mallostery, observed here for Hmg2 may be a widely used tactic of biological regulation with potential for development of therapeutic small molecules that induce selective misfolding.

SUBMITTER: Wangeline MA

PROVIDER: S-EPMC6153289 | biostudies-other | 2018 Sep

REPOSITORIES: biostudies-other

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"Mallostery"-ligand-dependent protein misfolding enables physiological regulation by ERAD.

Wangeline Margaret A MA Hampton Randolph Y RY

The Journal of biological chemistry 20180717 38

HMG-CoA reductase (HMGR) undergoes regulated degradation as part of feedback control of the sterol pathway. In yeast, the stability of the HMGR isozyme Hmg2 is controlled by the 20-carbon isoprenoid geranylgeranyl pyrophosphate (GGPP). Increasing GGPP levels cause more efficient degradation by the HMG-CoA reductase degradation (HRD) pathway, allowing for feedback regulation of HMGR. The HRD pathway is critical for the endoplasmic reticulum (ER)-associated degradation (ERAD) of misfolded ER prote ...[more]

PMID: 30018140

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Project description:Protein misfolding has been implicated in a large number of diseases termed protein- folding disorders (PFDs), which include Alzheimer's disease, Parkinson's disease, transmissible spongiform encephalopathies, familial amyloid polyneuropathy, Huntington's disease, and type II diabetes. In these diseases, large quantities of incorrectly folded proteins undergo aggregation, destroying brain cells and other tissues. The interplay between ligand binding and hydration is an important component of the formation of misfolded protein species. Hydration drives various biological processes, including protein folding, ligand binding, macromolecular assembly, enzyme kinetics, and signal transduction. The changes in hydration and packing, both when proteins fold correctly or when folding goes wrong, leading to PFDs, are examined through several biochemical, biophysical, and structural approaches. Although in many cases the binding of a ligand such as a nucleic acid helps to prevent misfolding and aggregation, there are several examples in which ligands induce misfolding and assembly into amyloids. This occurs simply because the formation of structured aggregates (such as protofibrillar and fibrillar amyloids) involves decreases in hydration, formation of a hydrogen-bond network in the secondary structure, and burying of nonpolar amino acid residues, processes that also occur in the normal folding landscape. In this Account, we describe the present knowledge of the folding and misfolding of different proteins, with a detailed emphasis on mammalian prion protein (PrP) and tumoral suppressor protein p53; we also explore how ligand binding and hydration together influence the fate of the proteins. Anfinsen's paradigm that the structure of a protein is determined by its amino acid sequence is to some extent contradicted by the observation that there are two isoforms of the prion protein with the same sequence: the cellular and the misfolded isoform. The cellular isoform of PrP has a disordered N-terminal domain and a highly flexible, not-well-packed C-terminal domain, which might account for its significant hydration. When PrP binds to biological molecules, such as glycosaminoglycans and nucleic acids, the disordered segments appear to fold and become less hydrated. Formation of the PrP-nucleic acid complex seems to accelerate the conversion of the cellular form of the protein into the disease-causing isoform. For p53, binding to some ligands, including nucleic acids, would prevent misfolding of the protein. Recently, several groups have begun to analyze the folding-misfolding of the individual domains of p53, but several questions remain unanswered. We discuss the implications of these findings for understanding the productive and incorrect folding pathways of these proteins in normal physiological states and in human disease, such as prion disorders and cancer. These studies are shown to lay the groundwork for the development of new drugs.

Dataset Information

"Mallostery"-ligand-dependent protein misfolding enables physiological regulation by ERAD.

Publications

"Mallostery"-ligand-dependent protein misfolding enables physiological regulation by ERAD.

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