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Article ; Online: Inhibitory CARs fail to protect from immediate T cell cytotoxicity.

Funk, Maximilian A / Heller, Gerwin / Waidhofer-Söllner, Petra / Leitner, Judith / Steinberger, Peter

Molecular therapy : the journal of the American Society of Gene Therapy

2024 Volume 32, Issue 4, Page(s) 982–999

Abstract: ... proposed as strategy to increase on-tumor specificity of CAR-T cell therapies. iCARs inhibit T cell ... activation upon antigen recognition and thereby program a Boolean NOT gate within the CAR-T cell. If cancer ... coexpressing T cells are supposed to kill cancer cells but not healthy cells expressing the CAR antigen ...

Abstract	Chimeric antigen receptors (CARs) equipped with an inhibitory signaling domain (iCARs) have been proposed as strategy to increase on-tumor specificity of CAR-T cell therapies. iCARs inhibit T cell activation upon antigen recognition and thereby program a Boolean NOT gate within the CAR-T cell. If cancer cells do not express the iCAR target antigen while it is highly expressed on healthy tissue, CAR/iCAR coexpressing T cells are supposed to kill cancer cells but not healthy cells expressing the CAR antigen. In this study, we employed a well-established reporter cell system to demonstrate high potency of iCAR constructs harboring BTLA-derived signaling domains. We then created CAR/iCAR combinations for the clinically relevant antigen pairs B7-H3/CD45 and CD123/CD19 and show potent reporter cell suppression by iCARs targeting CD45 or CD19. In primary human T cells αCD19-iCARs were capable of suppressing T cell proliferation and cytokine production. Surprisingly, the iCAR failed to veto immediate CAR-mediated cytotoxicity. Likewise, T cells overexpressing PD-1 or BTLA did not show impaired cytotoxicity toward ligand-expressing target cells, indicating that inhibitory signaling by these receptors does not mediate protection against cytotoxicity by CAR-T cells. Future approaches employing iCAR-equipped CAR-T cells for cancer therapy should therefore monitor off-tumor reactivity and potential CAR/iCAR-T cell dysfunction.
MeSH term(s)	Humans ; T-Lymphocytes ; Receptors, Chimeric Antigen/genetics ; Iron-Dextran Complex ; Immunotherapy, Adoptive ; Neoplasms/therapy ; Cell Line, Tumor
Chemical Substances	Receptors, Chimeric Antigen ; Iron-Dextran Complex (9004-66-4)
Language	English
Publishing date	2024-02-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1016/j.ymthe.2024.02.022
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Article ; Online: Primary anterior cruciate ligament repair-morphological and quantitative assessment by 7-T MRI and clinical outcome after 1.5 years.

Pachowsky, Milena L / Söllner, Stefan / Gelse, Kolja / Sambale, Jannik / Nagel, Armin M / Schett, Georg / Saake, Marc / Uder, Michael / Roemer, Frank W / Heiss, Rafael

European radiology

2024

Abstract: Objectives: The purpose of this study was to assess morphological and quantitative changes of the anterior cruciate ligament (ACL) and cartilage after ACL repair.: Methods: 7T MRI of the knee was acquired in 31 patients 1.5 years after ACL repair and ...

Abstract	Objectives: The purpose of this study was to assess morphological and quantitative changes of the anterior cruciate ligament (ACL) and cartilage after ACL repair. Methods: 7T MRI of the knee was acquired in 31 patients 1.5 years after ACL repair and in 13 controls. Proton density-weighted images with fat saturation (PD-fs) were acquired to assess ACL width, signal intensity, elongation, and fraying. T2/T2* mapping was performed for assessment of ACL and cartilage. Segmentation of the ACL, femoral, and tibial cartilage was carried out at 12 ROIs. The outcome evaluation consisted of the Lysholm Knee Score and International Knee Documentation Committee (IKDC) subjective score and clinical examination. Results: ACL showed a normal signal intensity in 96.8% and an increased width in 76.5% after repair. Fraying occurred in 22.6% without having an impact on the clinical outcome (Lysholm score: 90.39 ± 9.75, p = 0.76 compared to controls). T2 analysis of the ACL revealed no difference between patients and controls (p = 0.74). Compared to controls, assessment of the femoral and tibial cartilage showed a significant increase of T2* times in all ROIs, except at the posterolateral femur. Patients presented a good outcome in clinical examination with a Lysholm score of 87.19 ± 14.89 and IKDC of 80.23 ± 16.84. Conclusion: T2 mapping results suggest that the tissue composition of the ACL after repair is similar to that of a native ACL after surgery, whereas the ACL exhibits an increased width. Fraying of the ACL can occur without having any impact on functional outcomes. T2* analysis revealed early degradation at the cartilage. Clinical relevance statement: MRI represents a noninvasive diagnostic tool for the morphological and compositional assessment of the anterior cruciate ligament after repair, whereas knowledge about post-surgical alterations is crucial for adequate imaging interpretation. Key points: • There has been renewed interest in repairing the anterior cruciate ligament with a proximally torn ligament. • T2 times of the anterior cruciate ligament do not differ between anterior cruciate ligament repair patients and controls. • T2 mapping may serve as a surrogate for the evaluation of the anterior cruciate ligament after repair.
Language	English
Publishing date	2024-02-12
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1085366-2
ISSN	1432-1084 ; 0938-7994 ; 1613-3749
ISSN (online)	1432-1084
ISSN	0938-7994 ; 1613-3749
DOI	10.1007/s00330-024-10603-z
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Article ; Online: Multiplex gene analysis reveals T-cell and antibody-mediated rejection-specific upregulation of complement in renal transplants.

Vonbrunn, Eva / Ries, Tajana / Söllner, Stefan / Müller-Deile, Janina / Büttner-Herold, Maike / Amann, Kerstin / Daniel, Christoph

Scientific reports

2021 Volume 11, Issue 1, Page(s) 15464

Abstract: ... rejection (Ctrl), delayed graft function (DGF), acute T-cell-mediated (TCMR) or antibody-mediated rejection ...

Abstract	In renal transplantation, complement is involved in ischemia reperfusion injury, graft rejection and dysfunction. However, it is still unclear how induction of complement and its activation are initiated. Using allograft biopsies of a well-characterized cohort of 28 renal transplant patients with no rejection (Ctrl), delayed graft function (DGF), acute T-cell-mediated (TCMR) or antibody-mediated rejection (ABMR) we analyzed differences in complement reaction. For that mRNA was isolated from FFPE sections, quantified with a multiplex gene expression panel and correlated with transplant conditions and follow-up of patients. Additionally, inflammatory cells were quantified by multiplex immunohistochemistry. In allograft biopsies with TCMR and ABMR gene expression of C1QB was 2-4 fold elevated compared to Ctrl. In TCMR biopsies, mRNA counts of several complement-related genes including C1S, C3, CFB and complement regulators CFH, CR1 and SERPING1 were significantly increased compared to Ctrl. Interestingly, expression levels of about 75% of the analyzed complement related genes correlated with cold ischemia time (CIT) and markers of inflammation. In conclusion, this study suggest an important role of complement in transplant pathology which seems to be at least in part triggered by CIT. Multiplex mRNA analysis might be a useful method to refine diagnosis and explore new pathways involved in rejection.
MeSH term(s)	Adult ; Aged ; Allografts ; Biomarkers/metabolism ; Biopsy ; Body Mass Index ; Complement System Proteins/immunology ; Delayed Graft Function ; Female ; Gene Expression Profiling ; Graft Rejection ; Humans ; Inflammation ; Kidney/metabolism ; Kidney/pathology ; Kidney Transplantation/methods ; Male ; Middle Aged ; Principal Component Analysis ; RNA, Messenger/metabolism ; T-Lymphocytes/cytology ; Up-Regulation
Chemical Substances	Biomarkers ; RNA, Messenger ; Complement System Proteins (9007-36-7)
Language	English
Publishing date	2021-07-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-94954-3
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Article: Lack of Induction of RBD-Specific Neutralizing Antibodies despite Repeated Heterologous SARS-CoV-2 Vaccination Leading to Seroconversion and Establishment of T Cell-Specific Memory in a Patient in Remission of Multiple Myeloma.

Kratzer, Bernhard / Trapin, Doris / Gattinger, Pia / Oberhofer, Teresa / Sehgal, Al Nasar Ahmed / Waidhofer-Söllner, Petra / Rottal, Arno / Körmöczi, Ulrike / Grabmeier-Pfistershammer, Katharina / Kopetzky, Gerhard H / Tischer, Franz / Valenta, Rudolf / Pickl, Winfried F

Vaccines

2022 Volume 10, Issue 3

Abstract: ... monitored.: Results: No signs of seroconversion or T cellular memory were observed after the first "full ... specific antibody levels reaching 49 BAU/mL, mild S-peptide pool-specific T cell proliferation, effector cytokine ... production (IL-2, IL-13), and T cellular activation with increased numbers of CD3: Conclusions: Despite ...

Abstract	Background: Prophylactic vaccination against infectious diseases may induce a state of long-term protection in the otherwise healthy host. However, the situation is less predictable in immunocompromised patients and may require adjustment of vaccination schedules and/or basic therapy. Methods: A patient in full remission of multiple myeloma since the last three years and on long-term maintenance therapy with pomalidomide, a drug inhibiting angiogenesis and myeloma cell growth, was vaccinated twice with Comirnaty followed by two vaccinations with Vaxzevria. Seroconversion and SARS-CoV-2-specific cellular responses were monitored. Results: No signs of seroconversion or T cellular memory were observed after the first "full immunization" with Comirnaty. Consequently, long-term-maintenance therapy with Pomalidomide was stopped and two additional shots of Vaxzevria were administered after which the patient seroconverted with Spike(S)-protein specific antibody levels reaching 49 BAU/mL, mild S-peptide pool-specific T cell proliferation, effector cytokine production (IL-2, IL-13), and T cellular activation with increased numbers of CD3 Conclusions: Despite immunomonitoring-based adjustment of vaccination and/or therapy schedules vaccination success, with clear correlates of protection, the development of RBD-specific antibodies could not be achieved in the immunocompromised patient with current SARS-CoV-2 vaccines. Thus, our report emphasizes the need for improved active and passive immunization strategies for SARS-CoV-2 infections.
Language	English
Publishing date	2022-02-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines10030374
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Article ; Online: The energy sensor AMPK orchestrates metabolic and translational adaptation in expanding T helper cells.

Mayer, Katharina A / Smole, Ursula / Zhu, Ci / Derdak, Sophia / Minervina, Anastasia A / Salnikova, Maria / Witzeneder, Nadine / Christamentl, Anna / Boucheron, Nicole / Waidhofer-Söllner, Petra / Trauner, Michael / Hoermann, Gregor / Schmetterer, Klaus G / Mamedov, Ilgar Z / Bilban, Martin / Ellmeier, Wilfried / Pickl, Winfried F / Gualdoni, Guido A / Zlabinger, Gerhard J

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2021 Volume 35, Issue 4, Page(s) e21217

Abstract: The importance of cellular metabolic adaptation in inducing robust T cell responses is well ... established. However, the mechanism by which T cells link information regarding nutrient supply to clonal ... translational activity and, thus, orchestrates optimal expansion of T cells in vivo. AMPK deficiency did not ...

Abstract	The importance of cellular metabolic adaptation in inducing robust T cell responses is well established. However, the mechanism by which T cells link information regarding nutrient supply to clonal expansion and effector function is still enigmatic. Herein, we report that the metabolic sensor adenosine monophosphate-activated protein kinase (AMPK) is a critical link between cellular energy demand and translational activity and, thus, orchestrates optimal expansion of T cells in vivo. AMPK deficiency did not affect T cell fate decision, activation, or T effector cell generation; however, the magnitude of T cell responses in murine in vivo models of T cell activation was markedly reduced. This impairment was global, as all T helper cell subsets were similarly sensitive to loss of AMPK which resulted in reduced T cell accumulation in peripheral organs and reduced disease severity in pathophysiologically as diverse models as T cell transfer colitis and allergic airway inflammation. T cell receptor repertoire analysis confirmed similar clonotype frequencies in different lymphoid organs, thereby supporting the concept of a quantitative impairment in clonal expansion rather than a skewed qualitative immune response. In line with these findings, in-depth metabolic analysis revealed a decrease in T cell oxidative metabolism, and gene set enrichment analysis indicated a major reduction in ribosomal biogenesis and mRNA translation in AMPK-deficient T cells. We, thus, provide evidence that through its interference with these delicate processes, AMPK orchestrates the quantitative, but not the qualitative, manifestation of primary T cell responses in vivo.
MeSH term(s)	Adaptation, Physiological ; Adenylate Kinase/genetics ; Adenylate Kinase/metabolism ; Adoptive Transfer ; Animals ; CD4-Positive T-Lymphocytes ; Colitis/immunology ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation, Enzymologic ; Lymphocyte Activation ; Mice ; Mice, Knockout ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; T-Lymphocytes, Helper-Inducer/physiology ; T-Lymphocytes, Regulatory/physiology ; Th1 Cells/physiology ; Th17 Cells/physiology
Chemical Substances	DNA-Binding Proteins ; RNA, Messenger ; Rag2 protein, mouse ; Adenylate Kinase (EC 2.7.4.3)
Language	English
Publishing date	2021-04-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202001763RR
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Article ; Online: Multiplex gene analysis reveals T-cell and antibody-mediated rejection-specific upregulation of complement in renal transplants

Eva Vonbrunn / Tajana Ries / Stefan Söllner / Janina Müller-Deile / Maike Büttner-Herold / Kerstin Amann / Christoph Daniel

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 13

Abstract: ... rejection (Ctrl), delayed graft function (DGF), acute T-cell-mediated (TCMR) or antibody-mediated rejection ...

Abstract	Abstract In renal transplantation, complement is involved in ischemia reperfusion injury, graft rejection and dysfunction. However, it is still unclear how induction of complement and its activation are initiated. Using allograft biopsies of a well-characterized cohort of 28 renal transplant patients with no rejection (Ctrl), delayed graft function (DGF), acute T-cell-mediated (TCMR) or antibody-mediated rejection (ABMR) we analyzed differences in complement reaction. For that mRNA was isolated from FFPE sections, quantified with a multiplex gene expression panel and correlated with transplant conditions and follow-up of patients. Additionally, inflammatory cells were quantified by multiplex immunohistochemistry. In allograft biopsies with TCMR and ABMR gene expression of C1QB was 2-4 fold elevated compared to Ctrl. In TCMR biopsies, mRNA counts of several complement-related genes including C1S, C3, CFB and complement regulators CFH, CR1 and SERPING1 were significantly increased compared to Ctrl. Interestingly, expression levels of about 75% of the analyzed complement related genes correlated with cold ischemia time (CIT) and markers of inflammation. In conclusion, this study suggest an important role of complement in transplant pathology which seems to be at least in part triggered by CIT. Multiplex mRNA analysis might be a useful method to refine diagnosis and explore new pathways involved in rejection.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: Lack of Induction of RBD-Specific Neutralizing Antibodies despite Repeated Heterologous SARS-CoV-2 Vaccination Leading to Seroconversion and Establishment of T Cell-Specific Memory in a Patient in Remission of Multiple Myeloma

Bernhard Kratzer / Doris Trapin / Pia Gattinger / Teresa Oberhofer / Al Nasar Ahmed Sehgal / Petra Waidhofer-Söllner / Arno Rottal / Ulrike Körmöczi / Katharina Grabmeier-Pfistershammer / Gerhard H. Kopetzky / Franz Tischer / Rudolf Valenta / Winfried F. Pickl

Vaccines, Vol 10, Iss 374, p

2022 Volume 374

Abstract: ... monitored. Results: No signs of seroconversion or T cellular memory were observed after the first “full ... specific antibody levels reaching 49 BAU/mL, mild S-peptide pool-specific T cell proliferation, effector cytokine ... production (IL-2, IL-13), and T cellular activation with increased numbers of CD3 + CD4 + CD25 + T ...

Abstract	Background: Prophylactic vaccination against infectious diseases may induce a state of long-term protection in the otherwise healthy host. However, the situation is less predictable in immunocompromised patients and may require adjustment of vaccination schedules and/or basic therapy. Methods: A patient in full remission of multiple myeloma since the last three years and on long-term maintenance therapy with pomalidomide, a drug inhibiting angiogenesis and myeloma cell growth, was vaccinated twice with Comirnaty followed by two vaccinations with Vaxzevria. Seroconversion and SARS-CoV-2-specific cellular responses were monitored. Results: No signs of seroconversion or T cellular memory were observed after the first “full immunization” with Comirnaty. Consequently, long-term-maintenance therapy with Pomalidomide was stopped and two additional shots of Vaxzevria were administered after which the patient seroconverted with Spike(S)-protein specific antibody levels reaching 49 BAU/mL, mild S-peptide pool-specific T cell proliferation, effector cytokine production (IL-2, IL-13), and T cellular activation with increased numbers of CD3 + CD4 + CD25 + T cells as compared to vaccinated and non-vaccinated control subjects. However, despite suspension of immunosuppression and administration of in total four consecutive heterologous SARS-CoV-2 vaccine shots, the patient did not develop neutralizing RBD-specific antibodies. Conclusions: Despite immunomonitoring-based adjustment of vaccination and/or therapy schedules vaccination success, with clear correlates of protection, the development of RBD-specific antibodies could not be achieved in the immunocompromised patient with current SARS-CoV-2 vaccines. Thus, our report emphasizes the need for improved active and passive immunization strategies for SARS-CoV-2 infections.
Keywords	SARS-CoV-2 ; prophylactic vaccination ; multiple myeloma ; pomalidomide ; Medicine ; R
Subject code	610
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Zusammenhänge von Belastungsthemen und Coping-Strategien mit psychischer Gesundheit und Lebenszufriedenheit bei COPD – eine Mixed-Methods-Studie.

Köbler, Paul / Vogel, Ralf T / Joraschky, Peter / Söllner, Wolfgang

Psychotherapie, Psychosomatik, medizinische Psychologie

2024

Abstract: Understanding trigger and maintaining factors regarding psychiatric comorbidities in COPD is of great importance. In the presented mixed-methods study, qualitative interview data on burden experience and coping were related to psychiatric comorbidity ( ... ...

Title translation	Experiences of Burden and Coping Strategies and their Associations with Mental Health and Well-Being in COPD - a Mixed Methods Study.
Abstract	Understanding trigger and maintaining factors regarding psychiatric comorbidities in COPD is of great importance. In the presented mixed-methods study, qualitative interview data on burden experience and coping were related to psychiatric comorbidity (using PHQ-D) and quality of live (Positive Affect Negative Affect Schedulde, PANAS and Satisfaction with Life Scale, SWLS) and extended by the Freiburg Questionnaire on Coping with Illness (FKV-LIS). The two interview questions prompting narrative were 1.) "What is currently bothering you most?"; 2.) "How do you cope with your chronic disease in everyday life?" A total of 62 patients who were hospitalized due to COPD participated. The severity of physical impairment was assessed using GOLD stage and the Charlson Comorbidity Index (CCI). The interviews conducted were content analyzed and then quantified. The collected data were then compared between two groups with regard to mental distress. 13 themes of burden and 11 coping strategies were identified by content analysis. A total of 42 patients showed signs of mental distress, while 20 patients did not show signs of distress. There were no significant differences between the two groups in terms of sociodemographic characteristics and the severity of their physical symptoms. In the first interview question, the stressed group more frequently addressed issues related to death (35.7% versus 15.0%) and social stress (21.4% versus 0.0%). With respect to the second interview question, the nonstressed group was significantly more likely to mention strategies for consciously emphasizing positive emotions (70.0% versus 31.0%). In addition, higher scores on the FKV scales for depressive coping and trivialization and wishful thinking were evident in the stressed group. Quality of life and mental distress should be considered in clinical care for COPD. Interventions to influence illness perception and related coping styles are important, especially with regard to the development of a realistic and optimistic perspective on life and disease burden, as well as the inclusion of group and family therapeutic interventions.
Language	German
Publishing date	2024-03-16
Publishing country	Germany
Document type	English Abstract ; Journal Article
ZDB-ID	800571-0
ISSN	1439-1058 ; 0173-7937 ; 0937-2032
ISSN (online)	1439-1058
ISSN	0173-7937 ; 0937-2032
DOI	10.1055/a-2255-8695
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Article: A t-SNARE of the endocytic pathway must be activated for fusion.

Paumet, F / Brügger, B / Parlati, F / McNew, J A / Söllner, T H / Rothman, J E

The Journal of cell biology

2001 Volume 155, Issue 6, Page(s) 961–968

Abstract: The t-SNARE in a late Golgi compartment (Tlg2p) syntaxin is required for endocytosis and ... with two light chains, Tlg1p and Vti1p, to form a functional t-SNARE that mediates fusion, specifically ... with the v-SNAREs Snc1p and Snc2p. In vitro, this t-SNARE is inert, locked in a nonfunctional state, unless it is ...

Abstract	The t-SNARE in a late Golgi compartment (Tlg2p) syntaxin is required for endocytosis and localization of cycling proteins to the late Golgi compartment in yeast. We show here that Tlg2p assembles with two light chains, Tlg1p and Vti1p, to form a functional t-SNARE that mediates fusion, specifically with the v-SNAREs Snc1p and Snc2p. In vitro, this t-SNARE is inert, locked in a nonfunctional state, unless it is activated for fusion. Activation can be mediated by a peptide derived from the v-SNARE, which likely bypasses additional regulatory proteins in the cell. Locking t-SNAREs creates the potential for spatial and temporal regulation of fusion by signaling processes that unleash their fusion capacity.
MeSH term(s)	Amino Acid Sequence ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Endocytosis/physiology ; Fungal Proteins/genetics ; Fungal Proteins/metabolism ; Golgi Apparatus/metabolism ; Membrane Fusion/physiology ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Membrane Transport Proteins ; Molecular Sequence Data ; Protein Transport/physiology ; Qa-SNARE Proteins ; Qb-SNARE Proteins ; R-SNARE Proteins ; SNARE Proteins ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins ; Vesicular Transport Proteins
Chemical Substances	Carrier Proteins ; Fungal Proteins ; Membrane Proteins ; Membrane Transport Proteins ; Qa-SNARE Proteins ; Qb-SNARE Proteins ; R-SNARE Proteins ; SNARE Proteins ; SNC2 protein, S cerevisiae ; Saccharomyces cerevisiae Proteins ; TLG2 protein, S cerevisiae ; VTI1 protein, S cerevisiae ; Vesicular Transport Proteins
Language	English
Publishing date	2001-12-10
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	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.200104092
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Article: Functional architecture of an intracellular membrane t-SNARE.

Fukuda, R / McNew, J A / Weber, T / Parlati, F / Engel, T / Nickel, W / Rothman, J E / Söllner, T H

Nature

2000 Volume 407, Issue 6801, Page(s) 198–202

Abstract: ... protein receptors) located on the vesicle membrane (v-SNAREs) and the target membrane (t-SNAREs ... The assembled v-SNARE/t-SNARE complex consists of a bundle of four helices, of which one is supplied ... by the v-SNARE and the other three by the t-SNARE. For t-SNAREs on the plasma membrane, the protein syntaxin ...

Abstract	Lipid bilayer fusion is mediated by SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) located on the vesicle membrane (v-SNAREs) and the target membrane (t-SNAREs). The assembled v-SNARE/t-SNARE complex consists of a bundle of four helices, of which one is supplied by the v-SNARE and the other three by the t-SNARE. For t-SNAREs on the plasma membrane, the protein syntaxin supplies one helix and a SNAP-25 protein contributes the other two. Although there are numerous homologues of syntaxin on intracellular membranes, there are only two SNAP-25-related proteins in yeast, Sec9 and Spo20, both of which are localized to the plasma membrane and function in secretion and sporulation, respectively. What replaces SNAP-25 in t-SNAREs of intracellular membranes? Here we show that an intracellular t-SNARE is built from a 'heavy chain' homologous to syntaxin and two separate non-syntaxin 'light chains'. SNAP-25 may thus be the exception rather than the rule, having been derived from genes that encoded separate light chains that fused during evolution to produce a single gene encoding one protein with two helices.
MeSH term(s)	Escherichia coli ; Fungal Proteins/chemistry ; Fungal Proteins/physiology ; Intracellular Membranes/chemistry ; Intracellular Membranes/physiology ; Membrane Proteins/chemistry ; Membrane Proteins/physiology ; Nerve Tissue Proteins/chemistry ; Protein Binding ; Protein Conformation ; Protein Structure, Quaternary ; Qa-SNARE Proteins ; R-SNARE Proteins ; Recombinant Fusion Proteins/chemistry ; SNARE Proteins ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins ; Synaptosomal-Associated Protein 25 ; Vesicular Transport Proteins
Chemical Substances	Fungal Proteins ; Membrane Proteins ; Nerve Tissue Proteins ; Qa-SNARE Proteins ; R-SNARE Proteins ; Recombinant Fusion Proteins ; SNARE Proteins ; Saccharomyces cerevisiae Proteins ; Synaptosomal-Associated Protein 25 ; VAM3 protein, S cerevisiae ; Vesicular Transport Proteins ; YKT6 protein, S cerevisiae
Language	English
Publishing date	2000-09-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/35025084
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In stock of ZB MED Cologne/Königswinter

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Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito