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Article ; Online: Directed evolution in mammalian cells.

Hendel, Samuel J / Shoulders, Matthew D

2021 Volume 18, Issue 4, Page(s) 346–357

Abstract: Directed evolution experiments are typically carried out using in vitro systems, bacteria, or yeast-even when the goal is to probe or modulate mammalian biology. Performing directed evolution in systems that do not match the intended mammalian ... ...

Abstract	Directed evolution experiments are typically carried out using in vitro systems, bacteria, or yeast-even when the goal is to probe or modulate mammalian biology. Performing directed evolution in systems that do not match the intended mammalian environment severely constrains the scope and functionality of the targets that can be evolved. We review new platforms that are now making it possible to use the mammalian cell itself as the setting for directed evolution and present an overview of frontier challenges and high-impact targets for this approach.
MeSH term(s)	Animals ; Directed Molecular Evolution ; Humans ; Mutagenesis
Language	English
Publishing date	2021-04-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2169522-2
ISSN	1548-7105 ; 1548-7091
ISSN (online)	1548-7105
ISSN	1548-7091
DOI	10.1038/s41592-021-01090-x
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Article: Epistasis meets pleiotropy in shaping biophysical protein subspaces associated with antimicrobial resistance.

Ogbunugafor, C Brandon / Guerrero, Rafael F / Shakhnovich, Eugene I / Shoulders, Matthew D

bioRxiv : the preprint server for biology

2023

Abstract: Protein space is a rich analogy for genotype-phenotype maps, where amino acid sequence is organized into a high-dimensional space that highlights the connectivity between protein variants. It is a useful abstraction for understanding the process of ... ...

Abstract	Protein space is a rich analogy for genotype-phenotype maps, where amino acid sequence is organized into a high-dimensional space that highlights the connectivity between protein variants. It is a useful abstraction for understanding the process of evolution, and for efforts to engineer proteins towards desirable phenotypes. Few framings of protein space consider how higher-level protein phenotypes can be described in terms of their biophysical dimensions, nor do they rigorously interrogate how forces like epistasis-describing the nonlinear interaction between mutations and their phenotypic consequences-manifest across these dimensions. In this study, we deconstruct a low-dimensional protein space of a bacterial enzyme (dihydrofolate reductase; DHFR) into "subspaces" corresponding to a set of kinetic and thermodynamic traits [(
Language	English
Publishing date	2023-04-09
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.09.535490
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Article ; Online: Viral Evolution Shaped by Host Proteostasis Networks.

Yoon, Jimin / Patrick, Jessica E / Ogbunugafor, C Brandon / Shoulders, Matthew D

Annual review of virology

2023 Volume 10, Issue 1, Page(s) 77–98

Abstract: Understanding the factors that shape viral evolution is critical for developing effective antiviral strategies, accurately predicting viral evolution, and preventing pandemics. One fundamental determinant of viral evolution is the interplay between viral ...

Abstract	Understanding the factors that shape viral evolution is critical for developing effective antiviral strategies, accurately predicting viral evolution, and preventing pandemics. One fundamental determinant of viral evolution is the interplay between viral protein biophysics and the host machineries that regulate protein folding and quality control. Most adaptive mutations in viruses are biophysically deleterious, resulting in a viral protein product with folding defects. In cells, protein folding is assisted by a dynamic system of chaperones and quality control processes known as the proteostasis network. Host proteostasis networks can determine the fates of viral proteins with biophysical defects, either by assisting with folding or by targeting them for degradation. In this review, we discuss and analyze new discoveries revealing that host proteostasis factors can profoundly shape the sequence space accessible to evolving viral proteins. We also discuss the many opportunities for research progress proffered by the proteostasis perspective on viral evolution and adaptation.
MeSH term(s)	Proteostasis ; Protein Folding ; Molecular Chaperones/metabolism ; Viral Proteins/genetics ; Viral Proteins/metabolism ; Viruses/genetics
Chemical Substances	Molecular Chaperones ; Viral Proteins
Language	English
Publishing date	2023-04-18
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2764224-0
ISSN	2327-0578 ; 2327-056X
ISSN (online)	2327-0578
ISSN	2327-056X
DOI	10.1146/annurev-virology-100220-112120
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Article ; Online: Collagen misfolding mutations: the contribution of the unfolded protein response to the molecular pathology.

Bateman, John F / Shoulders, Matthew D / Lamandé, Shireen R

Connective tissue research

2022 Volume 63, Issue 3, Page(s) 210–227

Abstract: Mutations in collagen genes cause a broad range of connective tissue pathologies. Structural mutations that impact procollagen assembly or triple helix formation and stability are a common and important mutation class. How misfolded procollagens engage ... ...

Abstract	Mutations in collagen genes cause a broad range of connective tissue pathologies. Structural mutations that impact procollagen assembly or triple helix formation and stability are a common and important mutation class. How misfolded procollagens engage with the cellular proteostasis machinery and whether they can elicit a cytotoxic unfolded protein response (UPR) is a topic of considerable research interest. Such interest is well justified since modulating the UPR could offer a new approach to treat collagenopathies for which there are no current disease mechanism-targeting therapies. This review scrutinizes the evidence underpinning the view that endoplasmic reticulum stress and chronic UPR activation contributes significantly to the pathophysiology of the collagenopathies. While there is strong evidence that the UPR contributes to the pathology for collagen X misfolding mutations, the evidence that misfolding mutations in other collagen types induce a canonical, cytotoxic UPR is incomplete. To gain a more comprehensive understanding about how the UPR amplifies to pathology, and thus what types of manipulations of the UPR might have therapeutic relevance, much more information is needed about how specific misfolding mutation types engage differentially with the UPR and downstream signaling responses. Most importantly, since the capacity of the proteostasis machinery to respond to collagen misfolding is likely to vary between cell types, reflecting their functional roles in collagen and extracellular matrix biosynthesis, detailed studies on the UPR should focus as much as possible on the actual target cells involved in the collagen pathologies.
MeSH term(s)	Collagen/genetics ; Endoplasmic Reticulum Stress ; Mutation ; Pathology, Molecular ; Unfolded Protein Response
Chemical Substances	Collagen (9007-34-5)
Language	English
Publishing date	2022-02-26
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	185551-7
ISSN	1607-8438 ; 0091-1690 ; 0300-8207
ISSN (online)	1607-8438
ISSN	0091-1690 ; 0300-8207
DOI	10.1080/03008207.2022.2036735
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Article ; Online: Chemical Biology Framework to Illuminate Proteostasis.

Sebastian, Rebecca M / Shoulders, Matthew D

Annual review of biochemistry

2020 Volume 89, Page(s) 529–555

Abstract: Protein folding in the cell is mediated by an extensive network of >1,000 chaperones, quality control factors, and trafficking mechanisms collectively termed the proteostasis network. While the components and organization of this network are generally ... ...

Abstract	Protein folding in the cell is mediated by an extensive network of >1,000 chaperones, quality control factors, and trafficking mechanisms collectively termed the proteostasis network. While the components and organization of this network are generally well established, our understanding of how protein-folding problems are identified, how the network components integrate to successfully address challenges, and what types of biophysical issues each proteostasis network component is capable of addressing remains immature. We describe a chemical biology-informed framework for studying cellular proteostasis that relies on selection of interesting protein-folding problems and precise researcher control of proteostasis network composition and activities. By combining these methods with multifaceted strategies to monitor protein folding, degradation, trafficking, and aggregation in cells, researchers continue to rapidly generate new insights into cellular proteostasis.
MeSH term(s)	Animals ; CRISPR-Cas Systems ; Gene Expression Regulation ; Half-Life ; Heat-Shock Response/drug effects ; Humans ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism ; Molecular Probe Techniques ; Protein Aggregates ; Protein Engineering/methods ; Protein Folding/drug effects ; Protein Transport/drug effects ; Proteome/chemistry ; Proteome/genetics ; Proteome/metabolism ; Proteostasis/drug effects ; Proteostasis/genetics ; Proteostasis Deficiencies/genetics ; Proteostasis Deficiencies/metabolism ; Proteostasis Deficiencies/pathology ; Signal Transduction ; Small Molecule Libraries/chemical synthesis ; Small Molecule Libraries/pharmacology ; Unfolded Protein Response/drug effects
Chemical Substances	Molecular Chaperones ; Protein Aggregates ; Proteome ; Small Molecule Libraries
Language	English
Publishing date	2020-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	207924-0
ISSN	1545-4509 ; 0066-4154
ISSN (online)	1545-4509
ISSN	0066-4154
DOI	10.1146/annurev-biochem-013118-111552
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Article: Evolutionary druggability: leveraging low-dimensional fitness landscapes towards new metrics for antimicrobial applications.

Guerrero, Rafael F / Dorji, Tandin / Harris, Ra'Mal M / Shoulders, Matthew D / Ogbunugafor, C Brandon

bioRxiv : the preprint server for biology

2023

Abstract: The term "druggability" describes the molecular properties of drugs or targets in pharmacological interventions and is commonly used in work involving drug development for clinical applications. There are no current analogues for this notion that ... ...

Abstract	The term "druggability" describes the molecular properties of drugs or targets in pharmacological interventions and is commonly used in work involving drug development for clinical applications. There are no current analogues for this notion that quantify the drug-target interaction with respect to a given target variant's sensitivity across a breadth of drugs in a panel, or a given drug's range of effectiveness across alleles of a target protein. Using data from low-dimensional empirical fitness landscapes composed of 16
Language	English
Publishing date	2023-09-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.08.536116
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Article ; Online: Epistasis and pleiotropy shape biophysical protein subspaces associated with drug resistance.

Ogbunugafor, C Brandon / Guerrero, Rafael F / Miller-Dickson, Miles D / Shakhnovich, Eugene I / Shoulders, Matthew D

Physical review. E

2023 Volume 108, Issue 5-1, Page(s) 54408

Abstract	Protein space is a rich analogy for genotype-phenotype maps, where amino acid sequence is organized into a high-dimensional space that highlights the connectivity between protein variants. It is a useful abstraction for understanding the process of evolution, and for efforts to engineer proteins towards desirable phenotypes. Few mentions of protein space consider how protein phenotypes can be described in terms of their biophysical components, nor do they rigorously interrogate how forces like epistasis-describing the nonlinear interaction between mutations and their phenotypic consequences-manifest across these components. In this study, we deconstruct a low-dimensional protein space of a bacterial enzyme (dihydrofolate reductase; DHFR) into "subspaces" corresponding to a set of kinetic and thermodynamic traits [k_{cat}, K_{M}, K_{i}, and T_{m} (melting temperature)]. We then examine how combinations of three mutations (eight alleles in total) display pleiotropy, or unique effects on individual subspace traits. We examine protein spaces across three orthologous DHFR enzymes (Escherichia coli, Listeria grayi, and Chlamydia muridarum), adding a genotypic context dimension through which epistasis occurs across subspaces. In doing so, we reveal that protein space is a deceptively complex notion, and that future applications to bioengineering should consider how interactions between amino acid substitutions manifest across different phenotypic subspaces.
MeSH term(s)	Epistasis, Genetic ; Escherichia coli/metabolism ; Mutation ; Phenotype ; Tetrahydrofolate Dehydrogenase/genetics ; Tetrahydrofolate Dehydrogenase/chemistry ; Tetrahydrofolate Dehydrogenase/metabolism ; Drug Resistance
Chemical Substances	Tetrahydrofolate Dehydrogenase (EC 1.5.1.3)
Language	English
Publishing date	2023-12-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2844562-4
ISSN	2470-0053 ; 2470-0045
ISSN (online)	2470-0053
ISSN	2470-0045
DOI	10.1103/PhysRevE.108.054408
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Article ; Online: Targeting defective proteostasis in the collagenopathies.

Wong, Madeline Y / Shoulders, Matthew D

Current opinion in chemical biology

2019 Volume 50, Page(s) 80–88

Abstract: The collagenopathies are a diverse group of diseases caused primarily by mutations in collagen genes. The resulting disruptions in collagen biogenesis can impair development, cause cellular dysfunction, and severely impact connective tissues. Most ... ...

Abstract	The collagenopathies are a diverse group of diseases caused primarily by mutations in collagen genes. The resulting disruptions in collagen biogenesis can impair development, cause cellular dysfunction, and severely impact connective tissues. Most existing treatment options only address patient symptoms. Yet, while the disease-causing genes and proteins themselves are difficult to target, increasing evidence suggests that resculpting the intracellular proteostasis network, meaning the machineries responsible for producing and ensuring the integrity of collagen, could provide substantial benefit. We present a proteostasis-focused perspective on the collagenopathies, emphasizing progress toward understanding how mechanisms of collagen proteostasis are disrupted in disease. In parallel, we highlight recent advances in small molecule approaches to tune endoplasmic reticulum proteostasis that may prove useful in these disorders.
MeSH term(s)	Animals ; Collagen/biosynthesis ; Collagen/metabolism ; Endoplasmic Reticulum/metabolism ; Humans ; Proteostasis ; Proteostasis Deficiencies/metabolism
Chemical Substances	Collagen (9007-34-5)
Language	English
Publishing date	2019-04-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1439176-4
ISSN	1879-0402 ; 1367-5931
ISSN (online)	1879-0402
ISSN	1367-5931
DOI	10.1016/j.cbpa.2019.02.021
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Article ; Online: Genetic Engineering by DNA Recombineering.

Papa, Louis J / Shoulders, Matthew D

Current protocols in chemical biology

2019 Volume 11, Issue 3, Page(s) e70

Abstract: Recombineering inserts PCR products into DNA using homologous recombination. A pair of short homology arms (50 base pairs) on the ends of a PCR cassette target the cassette to its intended location. These homology arms can be easily introduced as 5' ... ...

Abstract	Recombineering inserts PCR products into DNA using homologous recombination. A pair of short homology arms (50 base pairs) on the ends of a PCR cassette target the cassette to its intended location. These homology arms can be easily introduced as 5' primer overhangs during the PCR reaction. The flexibility to choose almost any pair of homology arms enables the precise modification of virtually any DNA for purposes of sequence deletion, replacement, insertion, or point mutation. Recombineering often offers significant advantages relative to previous homologous recombination methods that require the construction of cassettes with large homology arms, and relative to traditional cloning methods that become intractable for large plasmids or DNA sequences. However, the tremendous number of variables, options, and pitfalls that can be encountered when designing and performing a recombineering protocol for the first time introduce barriers that can make recombineering a challenging technique for new users to adopt. This article focuses on three recombineering protocols we have found to be particularly robust, providing a detailed guide for choosing the simplest recombineering method for a given application and for performing and troubleshooting experiments. © 2019 by John Wiley & Sons, Inc.
MeSH term(s)	DNA/metabolism ; Escherichia coli/metabolism ; Gene Deletion ; Genetic Engineering/methods ; Mutagenesis, Insertional ; Plasmids/genetics ; Plasmids/metabolism ; Point Mutation ; Polymerase Chain Reaction ; Research Design
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2019-09-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2160-4762
ISSN (online)	2160-4762
DOI	10.1002/cpch.70
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Article ; Online: Using CRISPR/Cas9 to generate a heterozygous COL2A1 p.R719C iPSC line (MCRIi019-A-6) model of human precocious osteoarthritis.

Yammine, Kathryn M / Mirda Abularach, Sophia / Sampurno, Lisa / Bateman, John F / Lamandé, Shireen R / Shoulders, Matthew D

Stem cell research

2023 Volume 67, Page(s) 103020

Abstract: The human iPSC line MCRIi019-A-6 was generated using CRISPR/Cas9-mediated gene editing to introduce a heterozygous COL2A1 exon 33 c.2155C>T (p.R719C) mutation into the control human iPSC line MCRIi019-A. Both the edited and parental lines display typical ...

Abstract	The human iPSC line MCRIi019-A-6 was generated using CRISPR/Cas9-mediated gene editing to introduce a heterozygous COL2A1 exon 33 c.2155C>T (p.R719C) mutation into the control human iPSC line MCRIi019-A. Both the edited and parental lines display typical iPSC characteristics, including the expression of pluripotency markers, the ability to be differentiated into the three germ lines, and a normal karyotype. This cell line, along with the isogenic control line, can be used to study the molecular pathology of precocious osteoarthritis in a human model, more broadly understand type II collagenopathies, and explore novel therapeutic targets for this class of diseases.
MeSH term(s)	Humans ; Induced Pluripotent Stem Cells/metabolism ; CRISPR-Cas Systems ; Gene Editing ; Heterozygote ; Mutation ; Osteoarthritis/metabolism ; Collagen Type II/genetics
Chemical Substances	COL2A1 protein, human ; Collagen Type II
Language	English
Publishing date	2023-01-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2393143-7
ISSN	1876-7753 ; 1873-5061
ISSN (online)	1876-7753
ISSN	1873-5061
DOI	10.1016/j.scr.2023.103020
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