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Article ; Online: Sequence determinants of GLUT1-mediated accelerated-exchange transport: analysis by homology-scanning mutagenesis.

Vollers, Sabrina S / Carruthers, Anthony

2012 Volume 287, Issue 51, Page(s) 42533–42544

Abstract: The class 1 equilibrative glucose transporters GLUT1 and GLUT4 are structurally similar but catalyze distinct modes of transport. GLUT1 exhibits trans-acceleration, in which the presence of intracellular sugar stimulates the rate of unidirectional sugar ... ...

Abstract	The class 1 equilibrative glucose transporters GLUT1 and GLUT4 are structurally similar but catalyze distinct modes of transport. GLUT1 exhibits trans-acceleration, in which the presence of intracellular sugar stimulates the rate of unidirectional sugar uptake. GLUT4-mediated uptake is unaffected by intracellular sugar. Using homology-scanning mutagenesis in which domains of GLUT1 are substituted with equivalent domains from GLUT4 and vice versa, we show that GLUT1 transmembrane domain 6 is both necessary and sufficient for trans-acceleration. This region is not directly involved in GLUT1 binding of substrate or inhibitors. Rather, transmembrane domain 6 is part of two putative scaffold domains, which coordinate membrane-spanning amphipathic helices that form the sugar translocation pore. We propose that GLUT1 transmembrane domain 6 restrains import when intracellular sugar is absent by slowing transport-associated conformational changes.
MeSH term(s)	Amino Acid Sequence ; Biocatalysis ; Biological Transport ; Carbohydrate Metabolism ; Cell Membrane/metabolism ; Deoxyglucose/metabolism ; Glucose Transporter Type 1/chemistry ; Glucose Transporter Type 1/metabolism ; Glucose Transporter Type 4/chemistry ; Glucose Transporter Type 4/metabolism ; HEK293 Cells ; Humans ; Kinetics ; Models, Biological ; Molecular Sequence Data ; Mutagenesis/genetics ; Mutant Proteins/chemistry ; Mutant Proteins/metabolism ; Protein Structure, Tertiary ; Sequence Alignment ; Sequence Homology, Amino Acid ; Structure-Activity Relationship
Chemical Substances	Glucose Transporter Type 1 ; Glucose Transporter Type 4 ; Mutant Proteins ; Deoxyglucose (9G2MP84A8W)
Language	English
Publishing date	2012-10-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M112.369587
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Article ; Online: Class II major histocompatibility complex tetramer staining: progress, problems, and prospects.

Vollers, Sabrina S / Stern, Lawrence J

Immunology

2008 Volume 123, Issue 3, Page(s) 305–313

Abstract: The use of major histocompatibility complex (MHC) tetramers in the detection and analysis of antigen-specific T cells has become more widespread since its introduction 11 years ago. Early challenges in the application of tetramer staining to CD4+ T cells ...

Abstract	The use of major histocompatibility complex (MHC) tetramers in the detection and analysis of antigen-specific T cells has become more widespread since its introduction 11 years ago. Early challenges in the application of tetramer staining to CD4+ T cells centred around difficulties in the expression of various class II MHC allelic variants and the detection of low-frequency T cells in mixed populations. As many of the technical obstacles to class II MHC tetramer staining have been overcome, the focus has returned to uncertainties concerning how oligomer valency and T-cell receptor/MHC affinity affect tetramer binding. Such issues have become more important with an increase in the number of studies relying on direct ex vivo analysis of antigen-specific CD4+ T cells. In this review we discuss which problems in class II MHC tetramer staining have been solved to date, and which matters remain to be considered.
MeSH term(s)	Antibody Affinity ; CD4-Positive T-Lymphocytes/immunology ; Flow Cytometry/methods ; Histocompatibility Antigens Class II/analysis ; Histocompatibility Antigens Class II/immunology ; Humans ; Staining and Labeling/methods
Chemical Substances	Histocompatibility Antigens Class II
Language	English
Publishing date	2008-02-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/j.1365-2567.2007.02801.x
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Article: Class II major histocompatibility complex tetramer staining: progress, problems, and prospects

Vollers, Sabrina S / Stern, Lawrence J

Immunology. 2008 Mar., v. 123, no. 3

2008

Abstract	The use of major histocompatibility complex (MHC) tetramers in the detection and analysis of antigen-specific T cells has become more widespread since its introduction 11 years ago. Early challenges in the application of tetramer staining to CD4⁺ T cells centred around difficulties in the expression of various class II MHC allelic variants and the detection of low-frequency T cells in mixed populations. As many of the technical obstacles to class II MHC tetramer staining have been overcome, the focus has returned to uncertainties concerning how oligomer valency and T-cell receptor/MHC affinity affect tetramer binding. Such issues have become more important with an increase in the number of studies relying on direct ex vivo analysis of antigen-specific CD4⁺ T cells. In this review we discuss which problems in class II MHC tetramer staining have been solved to date, and which matters remain to be considered.
Keywords	flow cytometry
Language	English
Dates of publication	2008-03
Size	p. 305-313.
Publisher	Blackwell Publishing Ltd
Publishing place	Oxford, UK
Document type	Article
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/j.1365-2567.2007.02801.x
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Article ; Online: Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen.

Sesterhenn, Fabian / Galloux, Marie / Vollers, Sabrina S / Csepregi, Lucia / Yang, Che / Descamps, Delphyne / Bonet, Jaume / Friedensohn, Simon / Gainza, Pablo / Corthésy, Patricia / Chen, Man / Rosset, Stéphane / Rameix-Welti, Marie-Anne / Éléouët, Jean-François / Reddy, Sai T / Graham, Barney S / Riffault, Sabine / Correia, Bruno E

PLoS biology

2019 Volume 17, Issue 2, Page(s) e3000164

Abstract: Throughout the last several decades, vaccination has been key to prevent and eradicate infectious diseases. However, many pathogens (e.g., respiratory syncytial virus [RSV], influenza, dengue, and others) have resisted vaccine development efforts, ... ...

Abstract	Throughout the last several decades, vaccination has been key to prevent and eradicate infectious diseases. However, many pathogens (e.g., respiratory syncytial virus [RSV], influenza, dengue, and others) have resisted vaccine development efforts, largely because of the failure to induce potent antibody responses targeting conserved epitopes. Deep profiling of human B cells often reveals potent neutralizing antibodies that emerge from natural infection, but these specificities are generally subdominant (i.e., are present in low titers). A major challenge for next-generation vaccines is to overcome established immunodominance hierarchies and focus antibody responses on crucial neutralization epitopes. Here, we show that a computationally designed epitope-focused immunogen presenting a single RSV neutralization epitope elicits superior epitope-specific responses compared to the viral fusion protein. In addition, the epitope-focused immunogen efficiently boosts antibodies targeting the palivizumab epitope, resulting in enhanced neutralization. Overall, we show that epitope-focused immunogens can boost subdominant neutralizing antibody responses in vivo and reshape established antibody hierarchies.
MeSH term(s)	Animals ; Antibodies, Monoclonal, Humanized/chemistry ; Antibodies, Monoclonal, Humanized/immunology ; Antibodies, Neutralizing/biosynthesis ; Antibodies, Neutralizing/genetics ; Antibodies, Viral/biosynthesis ; Antibodies, Viral/genetics ; Cloning, Molecular ; Computer-Aided Design ; Epitopes/chemistry ; Epitopes/immunology ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Female ; Gene Expression ; Genetic Vectors/chemistry ; Genetic Vectors/metabolism ; Immunization/methods ; Immunogenicity, Vaccine ; Mice ; Mice, Inbred BALB C ; Nanoparticles/administration & dosage ; Nanoparticles/chemistry ; Palivizumab/chemistry ; Palivizumab/immunology ; Receptors, Antigen, B-Cell/chemistry ; Receptors, Antigen, B-Cell/genetics ; Receptors, Antigen, B-Cell/immunology ; Recombinant Fusion Proteins/administration & dosage ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/immunology ; Respiratory Syncytial Virus Vaccines/administration & dosage ; Respiratory Syncytial Virus Vaccines/biosynthesis ; Respiratory Syncytial Virus Vaccines/genetics ; Respiratory Syncytial Viruses/immunology ; Structural Homology, Protein ; Viral Fusion Proteins/administration & dosage ; Viral Fusion Proteins/chemistry ; Viral Fusion Proteins/genetics ; Viral Fusion Proteins/immunology
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antibodies, Neutralizing ; Antibodies, Viral ; Epitopes ; Receptors, Antigen, B-Cell ; Recombinant Fusion Proteins ; Respiratory Syncytial Virus Vaccines ; Viral Fusion Proteins ; motavizumab (50Y163LK8Q) ; Palivizumab (DQ448MW7KS)
Language	English
Publishing date	2019-02-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3000164
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Article: Determination of Peptide oligomerization state using rapid photochemical crosslinking.

Vollers, Sabrina S / Teplow, David B / Bitan, Gal

Methods in molecular biology (Clifton, N.J.)

2005 Volume 299, Page(s) 11–18

Abstract: The assembly of the amyloid beta-protein (Abeta) into neurotoxic oligomers and fibrils is a seminal pathogenic process in Alzheimer's disease (AD). Understanding the mechanisms of Abeta assembly could prove useful in the identification of therapeutic ... ...

Abstract	The assembly of the amyloid beta-protein (Abeta) into neurotoxic oligomers and fibrils is a seminal pathogenic process in Alzheimer's disease (AD). Understanding the mechanisms of Abeta assembly could prove useful in the identification of therapeutic targets. Owing to the metastable nature of Abeta oligomers, it is difficult to obtain interpretable data through application of classical methods, such as electrophoresis, chromatography, fluorescence, and light scattering. Here, we apply the method Photo-Induced Crosslinking of Unmodified Proteins (PICUP) to the study of Abeta oligomerization. This method directly produces covalent bonds among unmodified polypeptide chains through in situ generation of peptide free radicals. PICUP provides a snapshot of the native oligomerization state of proteins and can be used for assembly state analysis of a wide variety of peptides and proteins.
MeSH term(s)	Amyloid beta-Peptides/analysis ; Amyloid beta-Peptides/chemistry ; Organometallic Compounds ; Photochemistry/instrumentation ; Photochemistry/methods ; Photolysis
Chemical Substances	Amyloid beta-Peptides ; Organometallic Compounds ; tris(2,2'-bipyridyl)ruthenium(II)
Language	English
Publishing date	2005-09-01
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, P.H.S.
ISSN	1064-3745
ISSN	1064-3745
DOI	10.1385/1-59259-874-9:011
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Article ; Online: Author Correction: A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy.

Giordano-Attianese, Greta / Gainza, Pablo / Gray-Gaillard, Elise / Cribioli, Elisabetta / Shui, Sailan / Kim, Seonghoon / Kwak, Mi-Jeong / Vollers, Sabrina / Corria Osorio, Angel De Jesus / Reichenbach, Patrick / Bonet, Jaume / Oh, Byung-Ha / Irving, Melita / Coukos, George / Correia, Bruno E

Nature biotechnology

2020 Volume 38, Issue 4, Page(s) 503

Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

Abstract	An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Language	English
Publishing date	2020-03-04
Publishing country	United States
Document type	Published Erratum
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/s41587-020-0461-z
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Zs.A 2167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy.

Nature biotechnology

2020 Volume 38, Issue 4, Page(s) 426–432

Abstract: Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CAR-T-cell therapy, we computationally designed a chemically ... ...

Abstract	Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CAR-T-cell therapy, we computationally designed a chemically disruptable heterodimer (CDH) based on the binding of two human proteins. The CDH self-assembles, can be disrupted by a small-molecule drug and has a high-affinity protein interface with minimal amino acid deviation from wild-type human proteins. We incorporated the CDH into a synthetic heterodimeric CAR, called STOP-CAR, that has an antigen-recognition chain and a CD3ζ- and CD28-containing endodomain signaling chain. We tested STOP-CAR-T cells specific for two antigens in vitro and in vivo and found similar antitumor activity compared to second-generation (2G) CAR-T cells. Timed administration of the small-molecule drug dynamically inactivated the activity of STOP-CAR-T cells. Our work highlights the potential for structure-based design to add controllable elements to synthetic cellular therapies.
MeSH term(s)	Cell Engineering ; Cells, Cultured ; Humans ; Immunotherapy, Adoptive ; Jurkat Cells ; Lymphocyte Activation/drug effects ; PC-3 Cells ; Protein Binding ; Protein Engineering ; Protein Multimerization ; Receptors, Antigen, T-Cell/antagonists & inhibitors ; Receptors, Antigen, T-Cell/chemistry ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Chimeric Antigen/antagonists & inhibitors ; Receptors, Chimeric Antigen/chemistry ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/metabolism ; Signal Transduction ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemical Substances	Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen ; Small Molecule Libraries
Language	English
Publishing date	2020-02-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/s41587-019-0403-9
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Article ; Online: De novo protein design enables the precise induction of RSV-neutralizing antibodies.

Sesterhenn, Fabian / Yang, Che / Bonet, Jaume / Cramer, Johannes T / Wen, Xiaolin / Wang, Yimeng / Chiang, Chi-I / Abriata, Luciano A / Kucharska, Iga / Castoro, Giacomo / Vollers, Sabrina S / Galloux, Marie / Dheilly, Elie / Rosset, Stéphane / Corthésy, Patricia / Georgeon, Sandrine / Villard, Mélanie / Richard, Charles-Adrien / Descamps, Delphyne /

Delgado, Teresa / Oricchio, Elisa / Rameix-Welti, Marie-Anne / Más, Vicente / Ervin, Sean / Eléouët, Jean-François / Riffault, Sabine / Bates, John T / Julien, Jean-Philippe / Li, Yuxing / Jardetzky, Theodore / Krey, Thomas / Correia, Bruno E

Science (New York, N.Y.)

2020 Volume 368, Issue 6492

Abstract: De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses ... ...

Abstract	De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses remains a cornerstone for next-generation vaccines. Here, we present a protein design algorithm called TopoBuilder, with which we engineered epitope-focused immunogens displaying complex structural motifs. In both mice and nonhuman primates, cocktails of three de novo-designed immunogens induced robust neutralizing responses against the respiratory syncytial virus. Furthermore, the immunogens refocused preexisting antibody responses toward defined neutralization epitopes. Overall, our design approach opens the possibility of targeting specific epitopes for the development of vaccines and therapeutic antibodies and, more generally, will be applicable to the design of de novo proteins displaying complex functional motifs.
MeSH term(s)	Amino Acid Motifs ; Antibodies, Neutralizing/biosynthesis ; Computational Biology/methods ; Humans ; Immunodominant Epitopes/chemistry ; Immunodominant Epitopes/immunology ; Protein Conformation ; Protein Engineering/methods ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/immunology ; Respiratory Syncytial Virus Vaccines/chemistry ; Respiratory Syncytial Virus Vaccines/immunology ; Respiratory Syncytial Virus, Human/immunology ; Single-Domain Antibodies/chemistry ; Single-Domain Antibodies/immunology
Chemical Substances	Antibodies, Neutralizing ; Immunodominant Epitopes ; Recombinant Fusion Proteins ; Respiratory Syncytial Virus Vaccines ; Single-Domain Antibodies
Language	English
Publishing date	2020-06-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.aay5051
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Article: Elucidation of primary structure elements controlling early amyloid beta-protein oligomerization.

Bitan, Gal / Vollers, Sabrina S / Teplow, David B

The Journal of biological chemistry

2003 Volume 278, Issue 37, Page(s) 34882–34889

Abstract: Assembly of monomeric amyloid beta-protein (A beta) into oligomeric structures is an important pathogenetic feature of Alzheimer's disease. The oligomer size distributions of aggregate-free, low molecular weight A beta 40 and A beta 42 can be assessed ... ...

Abstract	Assembly of monomeric amyloid beta-protein (A beta) into oligomeric structures is an important pathogenetic feature of Alzheimer's disease. The oligomer size distributions of aggregate-free, low molecular weight A beta 40 and A beta 42 can be assessed quantitatively using the technique of photo-induced cross-linking of unmodified proteins. This approach revealed that low molecular weight A beta 40 is a mixture of monomer, dimer, trimer, and tetramer, in rapid equilibrium, whereas low molecular weight A beta 42 preferentially exists as pentamer/hexamer units (paranuclei), which self-associate to form larger oligomers. Here, photo-induced cross-linking of unmodified proteins was used to evaluate systematically the oligomerization of 34 physiologically relevant A beta alloforms, including those containing familial Alzheimer's disease-linked amino acid substitutions, naturally occurring N-terminal truncations, and modifications altering the charge, the hydrophobicity, or the conformation of the peptide. The most important structural feature controlling early oligomerization was the length of the C terminus. Specifically, the side-chain of residue 41 in A beta 42 was important both for effective formation of paranuclei and for self-association of paranuclei into larger oligomers. The side-chain of residue 42, and the C-terminal carboxyl group, affected paranucleus self-association. A beta 40 oligomerization was particularly sensitive to substitutions of Glu22 or Asp23 and to truncation of the N terminus, but not to substitutions of Phe19 or Ala21. A beta 42 oligomerization, in contrast, was largely unaffected by substitutions at positions 22 or 23 or by N-terminal truncations, but was affected significantly by substitutions of Phe19 or Ala21. These results reveal how specific regions and residues control A beta oligomerization and show that these controlling elements differ between A beta 40 and A beta 42.
MeSH term(s)	Alzheimer Disease/pathology ; Amino Acid Sequence ; Amyloid beta-Peptides/chemistry ; Dimerization ; Humans ; Molecular Weight
Chemical Substances	Amyloid beta-Peptides
Language	English
Publishing date	2003-07-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M300825200
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Article ; Online: Rosetta FunFolDes - A general framework for the computational design of functional proteins.

Bonet, Jaume / Wehrle, Sarah / Schriever, Karen / Yang, Che / Billet, Anne / Sesterhenn, Fabian / Scheck, Andreas / Sverrisson, Freyr / Veselkova, Barbora / Vollers, Sabrina / Lourman, Roxanne / Villard, Mélanie / Rosset, Stéphane / Krey, Thomas / Correia, Bruno E

PLoS computational biology

2018 Volume 14, Issue 11, Page(s) e1006623

Abstract: The robust computational design of functional proteins has the potential to deeply impact translational research and broaden our understanding of the determinants of protein function and stability. The low success rates of computational design protocols ... ...

Abstract	The robust computational design of functional proteins has the potential to deeply impact translational research and broaden our understanding of the determinants of protein function and stability. The low success rates of computational design protocols and the extensive in vitro optimization often required, highlight the challenge of designing proteins that perform essential biochemical functions, such as binding or catalysis. One of the most simplistic approaches for the design of function is to adopt functional motifs in naturally occurring proteins and transplant them to computationally designed proteins. The structural complexity of the functional motif largely determines how readily one can find host protein structures that are "designable", meaning that are likely to present the functional motif in the desired conformation. One promising route to enhance the "designability" of protein structures is to allow backbone flexibility. Here, we present a computational approach that couples conformational folding with sequence design to embed functional motifs into heterologous proteins-Rosetta Functional Folding and Design (FunFolDes). We performed extensive computational benchmarks, where we observed that the enforcement of functional requirements resulted in designs distant from the global energetic minimum of the protein. An observation consistent with several experimental studies that have revealed function-stability tradeoffs. To test the design capabilities of FunFolDes we transplanted two viral epitopes into distant structural templates including one de novo "functionless" fold, which represent two typical challenges where the designability problem arises. The designed proteins were experimentally characterized showing high binding affinities to monoclonal antibodies, making them valuable candidates for vaccine design endeavors. Overall, we present an accessible strategy to repurpose old protein folds for new functions. This may lead to important improvements on the computational design of proteins, with structurally complex functional sites, that can perform elaborate biochemical functions related to binding and catalysis.
MeSH term(s)	Amino Acid Motifs ; Antibodies, Monoclonal/chemistry ; Catalysis ; Computational Biology/methods ; Epitopes/chemistry ; Humans ; Models, Molecular ; Protein Binding ; Protein Engineering/methods ; Protein Folding ; Proteins/chemistry ; Software
Chemical Substances	Antibodies, Monoclonal ; Epitopes ; Proteins
Language	English
Publishing date	2018-11-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1006623
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