Scholars@Duke
Matt Scaglione

Matt Scaglione

Associate Professor of Molecular Genetics and Microbiology
Molecular Genetics and Microbiology
matt.scaglione@duke.edu
5128 MSRB III, Box 103853, Durham, NC 27710
5128 MSRB III, Durham, NC 27710

Scholarly Works - Journal articles

Nutrient and heat stress induce changes to the solubility of predicted prion-like proteins in Dictyostelium discoideum.

Journal article BMC Mol Cell Biol · March 12, 2026 BACKGROUND: Dictyostelium discoideum has a unique proteome among sequenced organisms that encodes nearly 10,000 homopolymeric amino acid tracts longer than 10 amino acids long. These repeats are composed of every amino acid except tryptophan with asparagin ... Full text Link to item Cite

Acute stress and multicellular development alter the solubility of the Dictyostelium Sup35 ortholog ERF3.

Journal article Microbiol Spectr · November 5, 2024 Among sequenced organisms, the genome of Dictyostelium discoideum is unique in that it encodes for a massive amount of repeat-rich sequences in the coding region of genes. This results in the Dictyostelium proteome encoding for thousands of repeat-rich pro ... Full text Link to item Cite

Viral vector gene delivery of the novel chaperone protein SRCP1 to modify insoluble protein in in vitro and in vivo models of ALS.

Journal article Gene Ther · June 2023 Protein misfolding and aggregation are shared features of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and protein quality control disruption contributes to neuronal toxicity. Therefore, reducing protein aggregation could hold ... Full text Link to item Cite

Mechanistic Insight into the Suppression of Polyglutamine Aggregation by SRCP1.

Journal article ACS Chem Biol · March 17, 2023 Protein aggregation is a hallmark of the polyglutamine diseases. One potential treatment for these diseases is suppression of polyglutamine aggregation. Previous work identified the cellular slime mold Dictyostelium discoideum as being naturally resistant ... Full text Link to item Cite

The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP.

Journal article J Biol Chem · May 2022 The spinocerebellar ataxias (SCAs) are a class of incurable diseases characterized by degeneration of the cerebellum that results in movement disorder. Recently, a new heritable form of SCA, spinocerebellar ataxia type 48 (SCA48), was attributed to dominan ... Full text Link to item Cite

Chemical Regulation of the Protein Quality Control E3 Ubiquitin Ligase C-Terminus of Hsc70 Interacting Protein (CHIP).

Journal article Chembiochem · March 18, 2022 The ubiquitin ligase C-terminus of Hsc70 interacting protein (CHIP) is an important regulator of proteostasis. Despite playing an important role in maintaining proteostasis, little progress has been made in developing small molecules that regulate ubiquiti ... Full text Link to item Cite

Insights on Microsatellite Characteristics, Evolution, and Function From the Social Amoeba Dictyostelium discoideum.

Journal article Front Neurosci · 2022 Microsatellites are repetitive sequences commonly found in the genomes of higher organisms. These repetitive sequences are prone to expansion or contraction, and when microsatellite expansion occurs in the regulatory or coding regions of genes this can res ... Full text Link to item Cite

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

Journal article Autophagy · January 2021 In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been ... Full text Link to item Cite

Development of a Positive Selection High Throughput Genetic Screen in Dictyostelium discoideum.

Journal article Front Cell Dev Biol · 2021 The cellular slime mold Dictyostelium discoideum is a powerful model organism that can be utilized to investigate human health and disease. One particular strength of Dictyostelium is that it can be utilized for high throughput genetic screens. For many ph ... Full text Link to item Cite

Assessing the necessity of a family of genes that encode small proteins in Dictyostelium discoideum development.

Journal article MicroPubl Biol · 2021 Dictyostelium discoideum's genome encodes for a large class of small proteins that are developmentally regulated. We deleted six of the genes that encode these proteins to determine if they play an essential role in Dictyostelium discoideum development. De ... Full text Link to item Cite

Dictyostelium discoideum as a Model for Investigating Neurodegenerative Diseases.

Journal article Front Cell Neurosci · 2021 The social amoeba Dictyostelium discoideum is a model organism that is used to investigate many cellular processes including chemotaxis, cell motility, cell differentiation, and human disease pathogenesis. While many single-cellular model systems lack homo ... Full text Link to item Cite

UbcH5 Interacts with Substrates to Participate in Lysine Selection with the E3 Ubiquitin Ligase CHIP.

Journal article Biochemistry · June 9, 2020 The E3 ubiquitin ligase C-terminus of Hsc70 interacting protein (CHIP) plays a critical role in regulating the ubiquitin-dependent degradation of misfolded proteins. CHIP mediates the ubiquitination of the α-amino-terminus of substrates with the E2 Ube2w a ... Full text Link to item Cite

Changes in protein function underlie the disease spectrum in patients with CHIP mutations.

Journal article J Biol Chem · December 13, 2019 Monogenetic disorders that cause cerebellar ataxia are characterized by defects in gait and atrophy of the cerebellum; however, patients often suffer from a spectrum of disease, complicating treatment options. Spinocerebellar ataxia autosomal recessive 16 ... Full text Link to item Cite

A Heat Shock Protein 48 (HSP48) Biomolecular Condensate Is Induced during Dictyostelium discoideum Development.

Journal article mSphere · June 19, 2019 The social amoeba Dictyostelium discoideum's proteome contains a vast array of simple sequence repeats, providing a unique model to investigate proteostasis. Upon conditions of cellular stress, D. discoideum undergoes a developmental process, transitioning ... Full text Link to item Cite

Changes in protein function underlies the disease spectrum in patients with CHIP mutations

Journal article · 2019 Monogenetic disorders that cause cerebellar ataxia are characterized by defects in gait and atrophy of the cerebellum; however, patients often suffer from a spectrum of disease, complicating treatment options. Spinocerebellar ataxia autosomal recessive 16 ... Full text Cite

SRCP1 Conveys Resistance to Polyglutamine Aggregation.

Journal article Mol Cell · July 19, 2018 The polyglutamine (polyQ) diseases are a group of nine neurodegenerative diseases caused by the expansion of a polyQ tract that results in protein aggregation. Unlike other model organisms, Dictyostelium discoideum is a proteostatic outlier, naturally enco ... Full text Link to item Cite

Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.

Journal article J Biol Chem · February 23, 2018 The accumulation of misfolded proteins promotes protein aggregation and neuronal death in many neurodegenerative diseases. To counteract misfolded protein accumulation, neurons have pathways that recognize and refold or degrade aggregation-prone proteins. ... Full text Link to item Cite

The ubiquitin conjugating enzyme Ube2W regulates solubility of the Huntington's disease protein, huntingtin.

Journal article Neurobiol Dis · January 2018 Huntington's disease (HD) is caused by a CAG repeat expansion that encodes a polyglutamine (polyQ) expansion in the HD disease protein, huntingtin (HTT). PolyQ expansion promotes misfolding and aggregation of mutant HTT (mHTT) within neurons. The cellular ... Full text Link to item Cite

Interaction of the polyglutamine protein ataxin-3 with Rad23 regulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3.

Journal article Hum Mol Genet · April 15, 2017 Polyglutamine (polyQ) repeat expansion in the deubiquitinase ataxin-3 causes neurodegeneration in Spinocerebellar Ataxia Type 3 (SCA3), one of nine inherited, incurable diseases caused by similar mutations. Ataxin-3's degradation is inhibited by its bindin ... Full text Link to item Cite

USP5 Is Dispensable for Monoubiquitin Maintenance in Drosophila.

Journal article J Biol Chem · April 22, 2016 Ubiquitination is a post-translational modification that regulates most cellular pathways and processes, including degradation of proteins by the proteasome. Substrate ubiquitination is controlled at various stages, including through its reversal by deubiq ... Full text Link to item Cite

Loss of the Ubiquitin-conjugating Enzyme UBE2W Results in Susceptibility to Early Postnatal Lethality and Defects in Skin, Immune, and Male Reproductive Systems.

Journal article J Biol Chem · February 5, 2016 UBE2W ubiquitinates N termini of proteins rather than internal lysine residues, showing a preference for substrates with intrinsically disordered N termini. The in vivo functions of this intriguing E2, however, remain unknown. We generated Ube2w germ line ... Full text Link to item Cite

The Social Amoeba Dictyostelium discoideum Is Highly Resistant to Polyglutamine Aggregation.

Journal article J Biol Chem · October 16, 2015 The expression, misfolding, and aggregation of long repetitive amino acid tracts are a major contributing factor in a number of neurodegenerative diseases, including C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia, fragile X tremor ataxia syn ... Full text Link to item Cite

A bipartite interaction between Hsp70 and CHIP regulates ubiquitination of chaperoned client proteins.

Journal article Structure · March 3, 2015 The ubiquitin ligase CHIP plays an important role in cytosolic protein quality control by ubiquitinating proteins chaperoned by Hsp70/Hsc70 and Hsp90, thereby targeting such substrate proteins for degradation. We present a 2.91 Å resolution structure of th ... Full text Link to item Cite

Allosteric regulation of deubiquitylase activity through ubiquitination.

Journal article Front Mol Biosci · 2015 Ataxin-3, the protein responsible for spinocerebellar ataxia type-3, is a cysteine protease that specifically cleaves poly-ubiquitin chains and participates in the ubiquitin proteasome pathway. The enzymatic activity resides in the N-terminal Josephin doma ... Full text Link to item Cite

Intrinsic disorder drives N-terminal ubiquitination by Ube2w.

Journal article Nat Chem Biol · January 2015 Ubiquitination of the αN-terminus of protein substrates has been reported sporadically since the early 1980s. However, the identity of an enzyme responsible for this unique ubiquitin (Ub) modification has only recently been elucidated. We show the Ub-conju ... Full text Link to item Cite

Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23.

Journal article Nat Commun · August 21, 2014 Polyglutamine repeat expansion in ataxin-3 causes neurodegeneration in the most common dominant ataxia, spinocerebellar ataxia type 3 (SCA3). Since reducing levels of disease proteins improves pathology in animals, we investigated how ataxin-3 is degraded. ... Full text Link to item Cite

Ubiquitination regulates the neuroprotective function of the deubiquitinase ataxin-3 in vivo.

Journal article J Biol Chem · November 29, 2013 Deubiquitinases (DUBs) are proteases that regulate various cellular processes by controlling protein ubiquitination. Cell-based studies indicate that the regulation of the activity of DUBs is important for homeostasis and is achieved by multiple mechanisms ... Full text Link to item Cite

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau.

Journal article J Clin Invest · October 2013 Aggregation of tau protein in the brain is associated with a class of neurodegenerative diseases known as tauopathies. FK506 binding protein 51 kDa (FKBP51, encoded by FKBP5) forms a mature chaperone complex with Hsp90 that prevents tau degradation. In thi ... Full text Link to item Cite

The E3 ubiquitin ligase CHIP and the molecular chaperone Hsc70 form a dynamic, tethered complex.

Journal article Biochemistry · August 13, 2013 The E3 ubiquitin ligase CHIP (C-terminus of Hsc70 Interacting Protein, a 70 kDa homodimer) binds to the molecular chaperone Hsc70 (a 70 kDa monomer), and this complex is important in both the ubiquitination of Hsc70 and the turnover of Hsc70-bound clients. ... Full text Link to item Cite

The ubiquitin-conjugating enzyme (E2) Ube2w ubiquitinates the N terminus of substrates.

Journal article J Biol Chem · June 28, 2013 Attachment of ubiquitin to substrate is typically thought to occur via formation of an isopeptide bond between the C-terminal glycine residue of ubiquitin and a lysine residue in the substrate. In vitro, Ube2w is nonreactive with free lysine yet readily ub ... Full text Link to item Cite

CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome.

Journal article Neuron · May 8, 2013 Fragile X-associated tremor ataxia syndrome (FXTAS) results from a CGG repeat expansion in the 5' UTR of FMR1. This repeat is thought to elicit toxicity as RNA, yet disease brains contain ubiquitin-positive neuronal inclusions, a pathologic hallmark of pro ... Full text Link to item Cite

Enzymatic production of mono-ubiquitinated proteins for structural studies: The example of the Josephin domain of ataxin-3.

Journal article FEBS Open Bio · 2013 Protein ubiquitination occurs through formation of an isopeptide bond between the C-terminal glycine of ubiquitin (Ub) and the ɛ-amino group of a substrate lysine residue. This post-translational modification, which occurs through the attachment of single ... Full text Link to item Cite

Ube2w and ataxin-3 coordinately regulate the ubiquitin ligase CHIP.

Journal article Mol Cell · August 19, 2011 The mechanisms by which ubiquitin ligases are regulated remain poorly understood. Here we describe a series of molecular events that coordinately regulate CHIP, a neuroprotective E3 implicated in protein quality control. Through their opposing activities, ... Full text Link to item Cite

The loop-less tmCdc34 E2 mutant defective in polyubiquitination in vitro and in vivo supports yeast growth in a manner dependent on Ubp14 and Cka2.

Journal article Cell Div · March 31, 2011 BACKGROUND: The S73/S97/loop motif is a hallmark of the Cdc34 family of E2 ubiquitin-conjugating enzymes that together with the SCF E3 ubiquitin ligases promote degradation of proteins involved in cell cycle and growth regulation. The inability of the loop ... Full text Link to item Cite

Activity and cellular functions of the deubiquitinating enzyme and polyglutamine disease protein ataxin-3 are regulated by ubiquitination at lysine 117.

Journal article J Biol Chem · December 10, 2010 Deubiquitinating enzymes (DUbs) play important roles in many ubiquitin-dependent pathways, yet how DUbs themselves are regulated is not well understood. Here, we provide insight into the mechanism by which ubiquitination directly enhances the activity of a ... Full text Link to item Cite

Ubiquitination directly enhances activity of the deubiquitinating enzyme ataxin-3.

Journal article EMBO J · February 18, 2009 Deubiquitinating enzymes (DUBs) control the ubiquitination status of proteins in various cellular pathways. Regulation of the activity of DUBs, which is critically important to cellular homoeostasis, can be achieved at the level of gene expression, protein ... Full text Link to item Cite

The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains.

Journal article J Biol Chem · September 26, 2008 Ubiquitin chain complexity in cells is likely regulated by a diverse set of deubiquitinating enzymes (DUBs) with distinct ubiquitin chain preferences. Here we show that the polyglutamine disease protein, ataxin-3, binds and cleaves ubiquitin chains in a ma ... Full text Link to item Cite

SCF E3-mediated autoubiquitination negatively regulates activity of Cdc34 E2 but plays a nonessential role in the catalytic cycle in vitro and in vivo.

Journal article Mol Cell Biol · August 2007 One of the several still unexplained aspects of the mechanism by which the Cdc34/SCF RING-type ubiquitin ligases work is the marked stimulation of Cdc34 autoubiquitination, a phenomenon of unknown mechanism and significance. In in vitro experiments with si ... Full text Link to item Cite

Certain pairs of ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s) synthesize nondegradable forked ubiquitin chains containing all possible isopeptide linkages.

Journal article J Biol Chem · June 15, 2007 It is generally assumed that a specific ubiquitin ligase (E3) links protein substrates to polyubiquitin chains containing a single type of isopeptide linkage, and that chains composed of linkages through Lys(48), but not through Lys(63), target proteins fo ... Full text Link to item Cite

Release of ubiquitin-charged Cdc34-S - Ub from the RING domain is essential for ubiquitination of the SCF(Cdc4)-bound substrate Sic1.

Journal article Cell · September 5, 2003 The S. cerevisiae SCF(Cdc4) is a prototype of RING-type SCF E3s, which recruit substrates for polyubiquitination by the Cdc34 ubiquitin-conjugating enzyme. Current models propose that Cdc34 ubiquitinates the substrate while remaining bound to the RING doma ... Full text Link to item Cite