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Article ; Online: Hold the fold: how delayed folding aids protein secretion.

McCaul, Nicholas / Braakman, Ineke

2022 Volume 41, Issue 23, Page(s) e112787

Abstract: In bacteria, N-terminal signal peptides mark proteins for transport across the plasma membrane. A recent study by Smets et al (2022) followed the folding of a pair of structural twins to shed light on how evolution has optimised the secretory process. ...

Abstract	In bacteria, N-terminal signal peptides mark proteins for transport across the plasma membrane. A recent study by Smets et al (2022) followed the folding of a pair of structural twins to shed light on how evolution has optimised the secretory process.
MeSH term(s)	Protein Transport ; Protein Sorting Signals ; Proteins ; Cell Membrane ; Protein Folding
Chemical Substances	Protein Sorting Signals ; Proteins
Language	English
Publishing date	2022-10-31
Publishing country	England
Document type	Journal Article
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2022112787
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Article ; Online: The Folding Pathway of ABC Transporter CFTR: Effective and Robust.

van der Sluijs, Peter / Hoelen, Hanneke / Schmidt, Andre / Braakman, Ineke

Journal of molecular biology

2024 , Page(s) 168591

Abstract: De novo protein folding into a native three-dimensional structure is indispensable for biological function, is instructed by its amino acid sequence, and occurs along a vectorial trajectory. The human proteome contains thousands of membrane-spanning ... ...

Abstract	De novo protein folding into a native three-dimensional structure is indispensable for biological function, is instructed by its amino acid sequence, and occurs along a vectorial trajectory. The human proteome contains thousands of membrane-spanning proteins, whose biosynthesis begins on endoplasmic reticulum-associated ribosomes. Nearly half of all membrane proteins traverse the membrane more than once, including therapeutically important protein families such as solute carriers, G-protein-coupled receptors, and ABC transporters. These mediate a variety of functions like signal transduction and solute transport and are often of vital importance for cell function and tissue homeostasis. Missense mutations in multispan membrane proteins can lead to misfolding and cause disease; an example is the ABC transporter Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Even though our understanding of multispan membrane-protein folding still is rather rudimental, the cumulative knowledge of 20 years of basic research on CFTR folding has led to development of drugs that modulate the misfolded protein. This has provided the prospect of a life without CF to the vast majority of patients. In this review we describe our understanding of the folding pathway of CFTR in cells, which is modular and tolerates many defects, making it effective and robust. We address how modulator drugs affect folding and function of CFTR, and distinguish protein stability from its folding process. Since the domain architecture of (mammalian) ABC transporters are highly conserved, we anticipate that the insights we discuss here for folding of CFTR may lay the groundwork for understanding the general rules of ABC-transporter folding.
Language	English
Publishing date	2024-04-26
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2024.168591
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Article ; Online: Redefining Hypo- and Hyper-Responding Phenotypes of CFTR Mutants for Understanding and Therapy.

Hillenaar, Tamara / Beekman, Jeffrey / van der Sluijs, Peter / Braakman, Ineke

International journal of molecular sciences

2022 Volume 23, Issue 23

Abstract: Mutations in CFTR cause misfolding and decreased or absent ion-channel function, resulting in the disease Cystic Fibrosis. Fortunately, a triple-modulator combination therapy (Trikafta) has been FDA-approved for 178 mutations, including all patients who ... ...

Abstract	Mutations in CFTR cause misfolding and decreased or absent ion-channel function, resulting in the disease Cystic Fibrosis. Fortunately, a triple-modulator combination therapy (Trikafta) has been FDA-approved for 178 mutations, including all patients who have F508del on one allele. That so many CFTR mutants respond well to modulators developed for a single mutation is due to the nature of the folding process of this multidomain protein. We have addressed the question 'What characterizes the exceptions: the mutants that functionally respond either not or extremely well'. A functional response is the product of the number of CFTR molecules on the cell surface, open probability, and conductivity of the CFTR chloride channel. By combining biosynthetic radiolabeling with protease-susceptibility assays, we have followed CF-causing mutants during the early and late stages of folding in the presence and absence of modulators. Most CFTR mutants showed typical biochemical responses for each modulator, such as a TMD1 conformational change or an increase in (cell-surface) stability, regardless of a functional response. These modulators thus should still be considered for hypo-responder genotypes. Understanding both biochemical and functional phenotypes of outlier mutations will boost our insights into CFTR folding and misfolding, and lead to improved therapeutic strategies.
Language	English
Publishing date	2022-12-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms232315170
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Article ; Online: Neil J. Bulleid (1960-2023), a virtuoso of protein folding and redox biology.

Braakman, Ineke / High, Stephen / Kadler, Karl / Sitia, Roberto / Tokatlidis, Kostas / Woodman, Philip

The EMBO journal

2023 Volume 42, Issue 17, Page(s) e115046

MeSH term(s)	Protein Folding ; Oxidation-Reduction ; Biology
Language	English
Publishing date	2023-08-02
Publishing country	England
Document type	Journal Article
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2023115046
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Article ; Online: Structure basis of CFTR folding, function and pharmacology.

Hwang, Tzyh-Chang / Braakman, Ineke / van der Sluijs, Peter / Callebaut, Isabelle

Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society

2022 Volume 22 Suppl 1, Page(s) S5–S11

Abstract: The root cause of cystic fibrosis (CF), the most common life-shortening genetic disease in the Caucasian population, is the loss of function of the CFTR protein, which serves as a phosphorylation-activated, ATP-gated anion channel in numerous epithelia- ... ...

Abstract	The root cause of cystic fibrosis (CF), the most common life-shortening genetic disease in the Caucasian population, is the loss of function of the CFTR protein, which serves as a phosphorylation-activated, ATP-gated anion channel in numerous epithelia-lining tissues. In the past decade, high-throughput drug screening has made a significant stride in developing highly effective CFTR modulators for the treatment of CF. Meanwhile, structural-biology studies have succeeded in solving the high-resolution three-dimensional (3D) structure of CFTR in different conformations. Here, we provide a brief overview of some striking features of CFTR folding, function and pharmacology, in light of its specific structural features within the ABC-transporter superfamily. A particular focus is given to CFTR's first nucleotide-binding domain (NBD1), because folding of NBD1 constitutes a bottleneck in the CFTR protein biogenesis pathway, and ATP binding to this domain plays a unique role in the functional stability of CFTR. Unraveling the molecular basis of CFTR folding, function, and pharmacology would inspire the development of next-generation mutation-specific CFTR modulators.
MeSH term(s)	Humans ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis/genetics ; Signal Transduction ; Mutation ; Adenosine Triphosphate ; Protein Folding
Chemical Substances	Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; Adenosine Triphosphate (8L70Q75FXE) ; CFTR protein, human
Language	English
Publishing date	2022-10-08
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2084724-5
ISSN	1873-5010 ; 1569-1993
ISSN (online)	1873-5010
ISSN	1569-1993
DOI	10.1016/j.jcf.2022.09.010
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Article ; Online: Transmembrane Helices 7 and 8 Confer Aggregation Sensitivity to the Cystic Fibrosis Transmembrane Conductance Regulator.

Kleizen, Bertrand / de Mattos, Eduardo / Papaioannou, Olga / Monti, Michele / Tartaglia, Gian Gaetano / van der Sluijs, Peter / Braakman, Ineke

International journal of molecular sciences

2023 Volume 24, Issue 21

Abstract: The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a large multi-spanning membrane protein that is susceptible to misfolding and aggregation. We have identified here the region responsible for this instability. Temperature-induced ... ...

Abstract	The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a large multi-spanning membrane protein that is susceptible to misfolding and aggregation. We have identified here the region responsible for this instability. Temperature-induced aggregation of C-terminally truncated versions of CFTR demonstrated that all truncations up to the second transmembrane domain (TMD2), including the R region, largely resisted aggregation. Limited proteolysis identified a folded structure that was prone to aggregation and consisted of TMD2 and at least part of the Regulatory Region R. Only when both TM7 (TransMembrane helix 7) and TM8 were present, TMD2 fragments became as aggregation-sensitive as wild-type CFTR, in line with increased thermo-instability of late CFTR nascent chains and in silico prediction of aggregation propensity. In accord, isolated TMD2 was degraded faster in cells than isolated TMD1. We conclude that TMD2 extended at its N-terminus with part of the R region forms a protease-resistant structure that induces heat instability in CFTR and may be responsible for its limited intracellular stability.
MeSH term(s)	Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Cell Membrane/metabolism ; Proteolysis ; Temperature ; Hot Temperature
Chemical Substances	Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
Language	English
Publishing date	2023-10-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms242115741
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Article ; Online: ABC-transporter CFTR folds with high fidelity through a modular, stepwise pathway

Im, Jisu / Hillenaar, Tamara / Yeoh, Hui Ying / Sahasrabudhe, Priyanka / Mijnders, Marjolein / van Willigen, Marcel / Hagos, Azib / de Mattos, Eduardo / van der Sluijs, Peter / Braakman, Ineke

Cell. Mol. Life Sci.. 2023 Jan., v. 80, no. 1 p.33-33

2023

Abstract: The question how proteins fold is especially pointed for large multi-domain, multi-spanning membrane proteins with complex topologies. We have uncovered the sequence of events that encompass proper folding of the ABC transporter CFTR in live cells by ... ...

Abstract	The question how proteins fold is especially pointed for large multi-domain, multi-spanning membrane proteins with complex topologies. We have uncovered the sequence of events that encompass proper folding of the ABC transporter CFTR in live cells by combining kinetic radiolabeling with protease-susceptibility assays. We found that CFTR folds in two clearly distinct stages. The first, co-translational, stage involves folding of the 2 transmembrane domains TMD1 and TMD2, plus one nucleotide-binding domain, NBD1. The second stage is a simultaneous, post-translational increase in protease resistance for both TMDs and NBD2, caused by assembly of these domains onto NBD1. Our assays probe every 2-3 residues (on average) in CFTR. This in-depth analysis at amino-acid level allows detailed analysis of domain folding and importantly also the next level: assembly of the domains into native, folded CFTR. Defects and changes brought about by medicines, chaperones, or mutations also are amenable to analysis. We here show that the well-known disease-causing mutation F508del, which established cystic fibrosis as protein-folding disease, caused co-translational misfolding of NBD1 but not TMD1 nor TMD2 in stage 1, leading to absence of stage-2 folding. Corrector drugs rescued stage 2 without rescuing NBD1. Likewise, the DxD motif in NBD1 that was identified to be required for export of CFTR from the ER we found to be required already upstream of export as CFTR mutated in this motif phenocopies F508del CFTR. The highly modular and stepwise folding process of such a large, complex protein explains the relatively high fidelity and correctability of its folding.
Keywords	ABC transporters ; amino acids ; cystic fibrosis ; exports ; mutation ; protein folding ; proteinases ; radiolabeling
Language	English
Dates of publication	2023-01
Size	p. 33.
Publishing place	Springer International Publishing
Document type	Article ; Online
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-022-04671-x
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Article ; Online: Entering a new era with Ero.

Braakman, Ineke

Nature reviews. Molecular cell biology

2009 Volume 10, Issue 8, Page(s) 503

MeSH term(s)	Disulfides/metabolism ; Endoplasmic Reticulum/enzymology ; Oxidation-Reduction ; Oxidoreductases Acting on Sulfur Group Donors/metabolism
Chemical Substances	Disulfides ; Oxidoreductases Acting on Sulfur Group Donors (EC 1.8.-)
Language	English
Publishing date	2009-07-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2031313-5
ISSN	1471-0080 ; 1471-0072
ISSN (online)	1471-0080
ISSN	1471-0072
DOI	10.1038/nrm2741
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Article ; Online: Protein quality control at the endoplasmic reticulum.

McCaffrey, Kathleen / Braakman, Ineke

Essays in biochemistry

2016 Volume 60, Issue 2, Page(s) 227–235

Abstract: The ER (endoplasmic reticulum) is the protein folding 'factory' of the secretory pathway. Virtually all proteins destined for the plasma membrane, the extracellular space or other secretory compartments undergo folding and maturation within the ER. The ... ...

Abstract	The ER (endoplasmic reticulum) is the protein folding 'factory' of the secretory pathway. Virtually all proteins destined for the plasma membrane, the extracellular space or other secretory compartments undergo folding and maturation within the ER. The ER hosts a unique PQC (protein quality control) system that allows specialized modifications such as glycosylation and disulfide bond formation essential for the correct folding and function of many secretory proteins. It is also the major checkpoint for misfolded or aggregation-prone proteins that may be toxic to the cell or extracellular environment. A failure of this system, due to aging or other factors, has therefore been implicated in a number of serious human diseases. In this article, we discuss several key features of ER PQC that maintain the health of the cellular secretome.
MeSH term(s)	Animals ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum-Associated Degradation ; Humans ; Models, Biological ; Protein Folding ; Proteins/metabolism ; Unfolded Protein Response
Chemical Substances	Proteins
Language	English
Publishing date	2016-10-15
Publishing country	England
Document type	Journal Article ; Review
ISSN	1744-1358 ; 0071-1365
ISSN (online)	1744-1358
ISSN	0071-1365
DOI	10.1042/EBC20160003
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Article ; Online: ABC-transporter CFTR folds with high fidelity through a modular, stepwise pathway.

Im, Jisu / Hillenaar, Tamara / Yeoh, Hui Ying / Sahasrabudhe, Priyanka / Mijnders, Marjolein / van Willigen, Marcel / Hagos, Azib / de Mattos, Eduardo / van der Sluijs, Peter / Braakman, Ineke

Cellular and molecular life sciences : CMLS

2023 Volume 80, Issue 1, Page(s) 33

Abstract	The question how proteins fold is especially pointed for large multi-domain, multi-spanning membrane proteins with complex topologies. We have uncovered the sequence of events that encompass proper folding of the ABC transporter CFTR in live cells by combining kinetic radiolabeling with protease-susceptibility assays. We found that CFTR folds in two clearly distinct stages. The first, co-translational, stage involves folding of the 2 transmembrane domains TMD1 and TMD2, plus one nucleotide-binding domain, NBD1. The second stage is a simultaneous, post-translational increase in protease resistance for both TMDs and NBD2, caused by assembly of these domains onto NBD1. Our assays probe every 2-3 residues (on average) in CFTR. This in-depth analysis at amino-acid level allows detailed analysis of domain folding and importantly also the next level: assembly of the domains into native, folded CFTR. Defects and changes brought about by medicines, chaperones, or mutations also are amenable to analysis. We here show that the well-known disease-causing mutation F508del, which established cystic fibrosis as protein-folding disease, caused co-translational misfolding of NBD1 but not TMD1 nor TMD2 in stage 1, leading to absence of stage-2 folding. Corrector drugs rescued stage 2 without rescuing NBD1. Likewise, the DxD motif in NBD1 that was identified to be required for export of CFTR from the ER we found to be required already upstream of export as CFTR mutated in this motif phenocopies F508del CFTR. The highly modular and stepwise folding process of such a large, complex protein explains the relatively high fidelity and correctability of its folding.
MeSH term(s)	Humans ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Protein Structure, Tertiary ; Cystic Fibrosis/genetics ; Mutation ; Peptide Hydrolases/genetics ; Protein Folding
Chemical Substances	Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; Peptide Hydrolases (EC 3.4.-) ; CFTR protein, human
Language	English
Publishing date	2023-01-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-022-04671-x
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