Jean-Marc Jeckelmann | University of Bern (original) (raw)
Papers by Jean-Marc Jeckelmann
Chimia, Dec 21, 2022
Amino acids are essential components of all living cells serving as building blocks of proteins, ... more Amino acids are essential components of all living cells serving as building blocks of proteins, as energy source, and as precursors of metabolites and signaling molecules. Amino acid transporters are membrane proteins that mediate the transfer of amino acids across the plasma membrane, and between compartments in cells, different cells and organs. The absence, overexpression or malfunction of specific amino acid transporters have been associated with human disease. One of the projects within the Swiss National Centre of Competence in Research (NCCR) TransCure was directed at SLC7 family amino acid transporters, with a particular focus on the heteromeric amino acid transporters 4F2hc-LAT1 (SLC3A2-SLC7A5) and 4F2hc-LAT2 (SLC3A2-SLC7A8), and the bacterial homologue AdiC. The project addressed questions of basic research (function and structure), pharmacology (identification of potent inhibitors and activators), and pre-clinical medicine (e.g., physiological role in the placenta) and disease models (e.g., tumor progression) of specific SLC7 family amino acid transporters. This review presents, summarizes and discusses selected main results obtained in this NCCR TransCure project.
Proceedings of the National Academy of Sciences of the United States of America, Jan 30, 2023
A crystal structure and aggregation properties of tri n butyl(octadecyl)phosphonium tet rafluorob... more A crystal structure and aggregation properties of tri n butyl(octadecyl)phosphonium tet rafluoroborate were studied. Palladium nanoparticles stabilized by this phosphonium salt ex hibit different catalytic activity in the Suzuki reaction, depending on the concentration of the stabilizing agent, which is related to the supramolecular organization of the Pd-phosphonium salt system.
CHIMIA
Amino acids are essential components of all living cells serving as building blocks of proteins, ... more Amino acids are essential components of all living cells serving as building blocks of proteins, as energy source, and as precursors of metabolites and signaling molecules. Amino acid transporters are membrane proteins that mediate the transfer of amino acids across the plasma membrane, and between compartments in cells, different cells and organs. The absence, overexpression or malfunction of specific amino acid transporters have been associated with human disease. One of the projects within the Swiss National Centre of Competence in Research (NCCR) TransCure was directed at SLC7 family amino acid transporters, with a particular focus on the heteromeric amino acid transporters 4F2hc-LAT1 (SLC3A2-SLC7A5) and 4F2hc-LAT2 (SLC3A2-SLC7A8), and the bacterial homologue AdiC. The project addressed questions of basic research (function and structure), pharmacology (identification of potent inhibitors and activators), and pre-clinical medicine (e.g., physiological role in the placenta) and d...
Views on the substrate binding pockets of YePEPT, GkPOTE310Q and PepTSt. The models of the substr... more Views on the substrate binding pockets of YePEPT, GkPOTE310Q and PepTSt. The models of the substrate-free YePEPT and the substrate-bound GkPOTE310Q and PepTSt were aligned. For comparison, the binding pockets are shown: YePEPT (A and D); GkPOTE310Q (B and E); and PepTSt (C and F). The conserved residues in the binding pockets (see Additional file 6: Table S2 for a detailed description) are shown as black sticks and the substrates are colored in yellow (alafosfalin; GkPOTE310Q; B and E) and green (Ala-Phe; PepTSt; C and F). In all panels the N- and C-terminal six-helix bundles (CÎą- backbones) are displayed in reddish and bluish colors, respectively. Note that the positions of the bundles and, most importantly, of the conserved residues are in good agreement. PDB ID codes of used models: 4W6V (YePEPT); 4IKZ (GkPOTE310Q); and 4D2C (PepTSt). (TIFF 5238 kb)
Groups of peptide transporter amino acid residues involved and potentially involved in alafosfali... more Groups of peptide transporter amino acid residues involved and potentially involved in alafosfalin and Ala-Phe dipeptide backbone binding. (DOC 37 kb)
Structural alignment of YePEPT with YbgH, GkPOTE310Q, PepTSo2 and PepTSt. Core structures are dis... more Structural alignment of YePEPT with YbgH, GkPOTE310Q, PepTSo2 and PepTSt. Core structures are displayed in blue (YePEPT), red (YbgH), green (GkPOTE310Q), magenta (PepTSo2) and yellow (PepTSt). RMSD values are 1.80 Å (for 342 residues; YbgH), 1.73 Å (for 391 residues; GkPOTE310Q), 1.78 Å (for 346 residues; PepTSo2) and 1.51 Å (for 336 residues; PepTSt). The HA and HB helices were omitted due to their intrinsic flexibility and are only displayed for YePEPT (light grey). PDB ID codes of used models: 4W6V (YePEPT); 4Q65 (YbgH); 4IKZ (GkPOTE310Q); 4LEP (PepTSo2); and 4APS (PepTSt). (TIFF 4602 kb)
Additional file 1: Supplementary Figures and Tables. Fig. S1. Schematic representation of the alt... more Additional file 1: Supplementary Figures and Tables. Fig. S1. Schematic representation of the alternating access mechanism. The major conformational changes and states of the transporter are shown, which are necessary to allow alternating substrate access from either side of the membrane to the substrate-binding site. Transporter, substrate and lipid molecules are colored in blue, orange and light brown, respectively. The different conformational states shown are a: outward-open, substrate-free; b: outward-open, substrate-bound; c: outward-facing, substrate occluded; d: substrate-bound, fully occluded; e: inward-facing, substrate occluded; f: inward-open, substrate-bound; g: inward-open, substrate-free; h: substrate-free, fully occluded. Fig. S2. Quality of the electron density of AdiC. All TMs are displayed as viewed from the membrane plane and boxed into TM-groups belonging to inverted repeats (left) and the dimerization interface (right). Starting and ending amino acid residues o...
Ki determination of YePEPT for Glu-Ala. The determined Ki is indicated (95 % confidence intervals... more Ki determination of YePEPT for Glu-Ala. The determined Ki is indicated (95 % confidence intervals: 28â 79 ÎźM). Error bars represent SEM from triplicates. One of two similar independent experiments is shown. (TIFF 64 kb)
Electron density map from the YePEPT crystal structure. Stereo view of the final 2 m|Fo|-D|Fc| el... more Electron density map from the YePEPT crystal structure. Stereo view of the final 2 m|Fo|-D|Fc| electron density map of YePEPT after refinement, contoured at 1.0 Ď . Helix 1 is shown. The YePEPT structure is depicted by stick models. (TIFF 4156 kb)
Data forsize exclusion chromatogram as shown in Fig. 3A, raw data for thermograms as shown in Fig... more Data forsize exclusion chromatogram as shown in Fig. 3A, raw data for thermograms as shown in Fig. 3C and raw data for SPA as shown in Fig. 3D.<br><br>
X-RAY STRUCTURES OF THE THREE L. LACTIS DIHYDROXYACETONE KINASE SUBUNITS AND OF A TRANSIENT INTER... more X-RAY STRUCTURES OF THE THREE L. LACTIS DIHYDROXYACETONE KINASE SUBUNITS AND OF A TRANSIENT INTER SUBUNIT COMPLEX Andreas Zurbriggen, Jean-Marc Jeckelmann, Sandra Christen, Christoph Bieniossek, Ulrich Baumann, and Bernhard Erni From the Departement für Chemie und Biochemie, Universität Bern, Freiestrasse 3, CH-3012 Bern, Switzerland Running Title: Dihydroxyacetone kinase These authors contributed equally to this work Address correspondence to: Bernhard Erni, Departement für Chemie und Biochemie, Universität Bern, Freiestrasse 3, CH-3012 Bern, Switzerland, Tel.: ++41-31-6314346; Fax: ++41-31-6314887; E-mail: erni@ibc.unibe.ch; Ulrich Baumann, Departement für Chemie und Biochemie, Universität Bern, Freiestrasse 3, CH-3012 Bern, Switzerland, Tel.:++41-31-6314320; Fax: ++41-31-6314887; E-mail: ulrich.baumann@ibc.unibe.ch
International Journal of Molecular Sciences, 2020
Heterodimeric amino acid transporters (HATs) are protein complexes mediating the transport of ami... more Heterodimeric amino acid transporters (HATs) are protein complexes mediating the transport of amino acids and derivatives thereof across biological membranes. HATs are composed of two subunits, a heavy and a light chain subunit belonging to the solute carrier (SLC) families SLC3 and SLC7. The human HAT 4F2hc-LAT2 is composed of the type-II membrane N-glycoprotein 4F2hc (SCL3A2) and the L-type amino acid transporter LAT2 (SLC7A8), which are covalently linked to each other by a conserved disulfide bridge. Whereas LAT2 catalyzes substrate transport, 4F2hc is important for the successful trafficking of the transporter to the plasma membrane. The overexpression, malfunction, or absence of 4F2hc-LAT2 is associated with human diseases, and therefore, this heterodimeric complex represents a potential drug target. The recombinant human 4F2hc-LAT2 can be functionally overexpressed in the methylotrophic yeast Pichia pastoris, and the protein can be purified. Here, we present the cryo-EM densit...
Subcellular Biochemistry, 2019
The Bacterial Phosphoenolpyruvate (PEP) : Sugar Phosphotransferase System (PTS) mediates the upta... more The Bacterial Phosphoenolpyruvate (PEP) : Sugar Phosphotransferase System (PTS) mediates the uptake and phosphorylation of carbohydrates, and controls the carbon- and nitrogen metabolism in response to the availability of sugars. PTS occur in eubacteria and in a few archaebacteria but not in animals and plants. All PTS comprise two cytoplasmic phosphotransferase proteins (EI and HPr) and a species-dependent, variable number of sugar-specific enzyme II complexes (IIA, IIB, IIC, IID). EI and HPr transfer phosphorylgroups from PEP to the IIA units. Cytoplasmic IIA and IIB units sequentially transfer phosphates to the sugar, which is transported by the IIC and IICIID integral membrane protein complexes. Phosphorylation by IIB and translocation by IIC(IID) are tightly coupled. The IIC(IID) sugar transporters of the PTS are in the focus of this review. There are four structurally different PTS transporter superfamilies (glucose, glucitol, ascorbate, mannose) . Crystal structures are available for transporters of two superfamilies: bcIICmal (MalT, 5IWS, 6BVG) and bcIICchb (ChbC, 3QNQ) of B. subtilis from the glucose family, and IICasc (UlaA, 4RP9, 5ZOV) of E. coli from the ascorbate superfamily . They are homodimers and each protomer has an independent transport pathway which functions by an elevator-type alternating-access mechanism. bcIICmal and bcIICchb have the same fold, IICasc has a completely different fold. Biochemical and biophysical data accumulated in the past with the transporters for mannitol (IICBAmtl) and glucose (IICBglc) are reviewed and discussed in the context of the bcIICmal crystal structures. The transporters of the mannose superfamily are dimers of protomers consisting of a IIC and a IID protein chain. The crystal structure is not known and the topology difficult to predict. Biochemical data indicate that the IICIID complex employs a different transport mechanism . Species specific IICIID serve as a gateway for the penetration of bacteriophage lambda DNA across, and insertion of class IIa bacteriocins into the inner membrane. PTS transporters are inserted into the membrane by SecYEG translocon and have specific lipid requirements. Immunoelectron- and fluorescence microscopy indicate a non-random distribution and supramolecular complexes of PTS proteins.
International Journal of Molecular Sciences, 2020
The human L-type amino acid transporters LAT1 and LAT2 mediate the transport of amino acids and a... more The human L-type amino acid transporters LAT1 and LAT2 mediate the transport of amino acids and amino acid derivatives across plasma membranes in a sodium-independent, obligatory antiport mode. In mammalian cells, LAT1 and LAT2 associate with the type-II membrane N-glycoprotein 4F2hc to form heteromeric amino acid transporters (HATs). The glycosylated ancillary protein 4F2hc is known to be important for successful trafficking of the unglycosylated transporters to the plasma membrane. The heavy (i.e., 4F2hc) and light (i.e., LAT1 and LAT2) chains belong to the solute carrier (SLC) families SLC3 and SLC7, and are covalently linked by a conserved disulfide bridge. Overexpression, absence, or malfunction of certain HATs is associated with human diseases and HATs are therefore considered therapeutic targets. Here, we present a comparative, functional characterization of the HATs 4F2hc-LAT1 and 4F2hc-LAT2, and their light chains LAT1 and LAT2. For this purpose, the HATs and the light chai...
Chimia, Dec 21, 2022
Amino acids are essential components of all living cells serving as building blocks of proteins, ... more Amino acids are essential components of all living cells serving as building blocks of proteins, as energy source, and as precursors of metabolites and signaling molecules. Amino acid transporters are membrane proteins that mediate the transfer of amino acids across the plasma membrane, and between compartments in cells, different cells and organs. The absence, overexpression or malfunction of specific amino acid transporters have been associated with human disease. One of the projects within the Swiss National Centre of Competence in Research (NCCR) TransCure was directed at SLC7 family amino acid transporters, with a particular focus on the heteromeric amino acid transporters 4F2hc-LAT1 (SLC3A2-SLC7A5) and 4F2hc-LAT2 (SLC3A2-SLC7A8), and the bacterial homologue AdiC. The project addressed questions of basic research (function and structure), pharmacology (identification of potent inhibitors and activators), and pre-clinical medicine (e.g., physiological role in the placenta) and disease models (e.g., tumor progression) of specific SLC7 family amino acid transporters. This review presents, summarizes and discusses selected main results obtained in this NCCR TransCure project.
Proceedings of the National Academy of Sciences of the United States of America, Jan 30, 2023
A crystal structure and aggregation properties of tri n butyl(octadecyl)phosphonium tet rafluorob... more A crystal structure and aggregation properties of tri n butyl(octadecyl)phosphonium tet rafluoroborate were studied. Palladium nanoparticles stabilized by this phosphonium salt ex hibit different catalytic activity in the Suzuki reaction, depending on the concentration of the stabilizing agent, which is related to the supramolecular organization of the Pd-phosphonium salt system.
CHIMIA
Amino acids are essential components of all living cells serving as building blocks of proteins, ... more Amino acids are essential components of all living cells serving as building blocks of proteins, as energy source, and as precursors of metabolites and signaling molecules. Amino acid transporters are membrane proteins that mediate the transfer of amino acids across the plasma membrane, and between compartments in cells, different cells and organs. The absence, overexpression or malfunction of specific amino acid transporters have been associated with human disease. One of the projects within the Swiss National Centre of Competence in Research (NCCR) TransCure was directed at SLC7 family amino acid transporters, with a particular focus on the heteromeric amino acid transporters 4F2hc-LAT1 (SLC3A2-SLC7A5) and 4F2hc-LAT2 (SLC3A2-SLC7A8), and the bacterial homologue AdiC. The project addressed questions of basic research (function and structure), pharmacology (identification of potent inhibitors and activators), and pre-clinical medicine (e.g., physiological role in the placenta) and d...
Views on the substrate binding pockets of YePEPT, GkPOTE310Q and PepTSt. The models of the substr... more Views on the substrate binding pockets of YePEPT, GkPOTE310Q and PepTSt. The models of the substrate-free YePEPT and the substrate-bound GkPOTE310Q and PepTSt were aligned. For comparison, the binding pockets are shown: YePEPT (A and D); GkPOTE310Q (B and E); and PepTSt (C and F). The conserved residues in the binding pockets (see Additional file 6: Table S2 for a detailed description) are shown as black sticks and the substrates are colored in yellow (alafosfalin; GkPOTE310Q; B and E) and green (Ala-Phe; PepTSt; C and F). In all panels the N- and C-terminal six-helix bundles (CÎą- backbones) are displayed in reddish and bluish colors, respectively. Note that the positions of the bundles and, most importantly, of the conserved residues are in good agreement. PDB ID codes of used models: 4W6V (YePEPT); 4IKZ (GkPOTE310Q); and 4D2C (PepTSt). (TIFF 5238 kb)
Groups of peptide transporter amino acid residues involved and potentially involved in alafosfali... more Groups of peptide transporter amino acid residues involved and potentially involved in alafosfalin and Ala-Phe dipeptide backbone binding. (DOC 37 kb)
Structural alignment of YePEPT with YbgH, GkPOTE310Q, PepTSo2 and PepTSt. Core structures are dis... more Structural alignment of YePEPT with YbgH, GkPOTE310Q, PepTSo2 and PepTSt. Core structures are displayed in blue (YePEPT), red (YbgH), green (GkPOTE310Q), magenta (PepTSo2) and yellow (PepTSt). RMSD values are 1.80 Å (for 342 residues; YbgH), 1.73 Å (for 391 residues; GkPOTE310Q), 1.78 Å (for 346 residues; PepTSo2) and 1.51 Å (for 336 residues; PepTSt). The HA and HB helices were omitted due to their intrinsic flexibility and are only displayed for YePEPT (light grey). PDB ID codes of used models: 4W6V (YePEPT); 4Q65 (YbgH); 4IKZ (GkPOTE310Q); 4LEP (PepTSo2); and 4APS (PepTSt). (TIFF 4602 kb)
Additional file 1: Supplementary Figures and Tables. Fig. S1. Schematic representation of the alt... more Additional file 1: Supplementary Figures and Tables. Fig. S1. Schematic representation of the alternating access mechanism. The major conformational changes and states of the transporter are shown, which are necessary to allow alternating substrate access from either side of the membrane to the substrate-binding site. Transporter, substrate and lipid molecules are colored in blue, orange and light brown, respectively. The different conformational states shown are a: outward-open, substrate-free; b: outward-open, substrate-bound; c: outward-facing, substrate occluded; d: substrate-bound, fully occluded; e: inward-facing, substrate occluded; f: inward-open, substrate-bound; g: inward-open, substrate-free; h: substrate-free, fully occluded. Fig. S2. Quality of the electron density of AdiC. All TMs are displayed as viewed from the membrane plane and boxed into TM-groups belonging to inverted repeats (left) and the dimerization interface (right). Starting and ending amino acid residues o...
Ki determination of YePEPT for Glu-Ala. The determined Ki is indicated (95 % confidence intervals... more Ki determination of YePEPT for Glu-Ala. The determined Ki is indicated (95 % confidence intervals: 28â 79 ÎźM). Error bars represent SEM from triplicates. One of two similar independent experiments is shown. (TIFF 64 kb)
Electron density map from the YePEPT crystal structure. Stereo view of the final 2 m|Fo|-D|Fc| el... more Electron density map from the YePEPT crystal structure. Stereo view of the final 2 m|Fo|-D|Fc| electron density map of YePEPT after refinement, contoured at 1.0 Ď . Helix 1 is shown. The YePEPT structure is depicted by stick models. (TIFF 4156 kb)
Data forsize exclusion chromatogram as shown in Fig. 3A, raw data for thermograms as shown in Fig... more Data forsize exclusion chromatogram as shown in Fig. 3A, raw data for thermograms as shown in Fig. 3C and raw data for SPA as shown in Fig. 3D.<br><br>
X-RAY STRUCTURES OF THE THREE L. LACTIS DIHYDROXYACETONE KINASE SUBUNITS AND OF A TRANSIENT INTER... more X-RAY STRUCTURES OF THE THREE L. LACTIS DIHYDROXYACETONE KINASE SUBUNITS AND OF A TRANSIENT INTER SUBUNIT COMPLEX Andreas Zurbriggen, Jean-Marc Jeckelmann, Sandra Christen, Christoph Bieniossek, Ulrich Baumann, and Bernhard Erni From the Departement für Chemie und Biochemie, Universität Bern, Freiestrasse 3, CH-3012 Bern, Switzerland Running Title: Dihydroxyacetone kinase These authors contributed equally to this work Address correspondence to: Bernhard Erni, Departement für Chemie und Biochemie, Universität Bern, Freiestrasse 3, CH-3012 Bern, Switzerland, Tel.: ++41-31-6314346; Fax: ++41-31-6314887; E-mail: erni@ibc.unibe.ch; Ulrich Baumann, Departement für Chemie und Biochemie, Universität Bern, Freiestrasse 3, CH-3012 Bern, Switzerland, Tel.:++41-31-6314320; Fax: ++41-31-6314887; E-mail: ulrich.baumann@ibc.unibe.ch
International Journal of Molecular Sciences, 2020
Heterodimeric amino acid transporters (HATs) are protein complexes mediating the transport of ami... more Heterodimeric amino acid transporters (HATs) are protein complexes mediating the transport of amino acids and derivatives thereof across biological membranes. HATs are composed of two subunits, a heavy and a light chain subunit belonging to the solute carrier (SLC) families SLC3 and SLC7. The human HAT 4F2hc-LAT2 is composed of the type-II membrane N-glycoprotein 4F2hc (SCL3A2) and the L-type amino acid transporter LAT2 (SLC7A8), which are covalently linked to each other by a conserved disulfide bridge. Whereas LAT2 catalyzes substrate transport, 4F2hc is important for the successful trafficking of the transporter to the plasma membrane. The overexpression, malfunction, or absence of 4F2hc-LAT2 is associated with human diseases, and therefore, this heterodimeric complex represents a potential drug target. The recombinant human 4F2hc-LAT2 can be functionally overexpressed in the methylotrophic yeast Pichia pastoris, and the protein can be purified. Here, we present the cryo-EM densit...
Subcellular Biochemistry, 2019
The Bacterial Phosphoenolpyruvate (PEP) : Sugar Phosphotransferase System (PTS) mediates the upta... more The Bacterial Phosphoenolpyruvate (PEP) : Sugar Phosphotransferase System (PTS) mediates the uptake and phosphorylation of carbohydrates, and controls the carbon- and nitrogen metabolism in response to the availability of sugars. PTS occur in eubacteria and in a few archaebacteria but not in animals and plants. All PTS comprise two cytoplasmic phosphotransferase proteins (EI and HPr) and a species-dependent, variable number of sugar-specific enzyme II complexes (IIA, IIB, IIC, IID). EI and HPr transfer phosphorylgroups from PEP to the IIA units. Cytoplasmic IIA and IIB units sequentially transfer phosphates to the sugar, which is transported by the IIC and IICIID integral membrane protein complexes. Phosphorylation by IIB and translocation by IIC(IID) are tightly coupled. The IIC(IID) sugar transporters of the PTS are in the focus of this review. There are four structurally different PTS transporter superfamilies (glucose, glucitol, ascorbate, mannose) . Crystal structures are available for transporters of two superfamilies: bcIICmal (MalT, 5IWS, 6BVG) and bcIICchb (ChbC, 3QNQ) of B. subtilis from the glucose family, and IICasc (UlaA, 4RP9, 5ZOV) of E. coli from the ascorbate superfamily . They are homodimers and each protomer has an independent transport pathway which functions by an elevator-type alternating-access mechanism. bcIICmal and bcIICchb have the same fold, IICasc has a completely different fold. Biochemical and biophysical data accumulated in the past with the transporters for mannitol (IICBAmtl) and glucose (IICBglc) are reviewed and discussed in the context of the bcIICmal crystal structures. The transporters of the mannose superfamily are dimers of protomers consisting of a IIC and a IID protein chain. The crystal structure is not known and the topology difficult to predict. Biochemical data indicate that the IICIID complex employs a different transport mechanism . Species specific IICIID serve as a gateway for the penetration of bacteriophage lambda DNA across, and insertion of class IIa bacteriocins into the inner membrane. PTS transporters are inserted into the membrane by SecYEG translocon and have specific lipid requirements. Immunoelectron- and fluorescence microscopy indicate a non-random distribution and supramolecular complexes of PTS proteins.
International Journal of Molecular Sciences, 2020
The human L-type amino acid transporters LAT1 and LAT2 mediate the transport of amino acids and a... more The human L-type amino acid transporters LAT1 and LAT2 mediate the transport of amino acids and amino acid derivatives across plasma membranes in a sodium-independent, obligatory antiport mode. In mammalian cells, LAT1 and LAT2 associate with the type-II membrane N-glycoprotein 4F2hc to form heteromeric amino acid transporters (HATs). The glycosylated ancillary protein 4F2hc is known to be important for successful trafficking of the unglycosylated transporters to the plasma membrane. The heavy (i.e., 4F2hc) and light (i.e., LAT1 and LAT2) chains belong to the solute carrier (SLC) families SLC3 and SLC7, and are covalently linked by a conserved disulfide bridge. Overexpression, absence, or malfunction of certain HATs is associated with human diseases and HATs are therefore considered therapeutic targets. Here, we present a comparative, functional characterization of the HATs 4F2hc-LAT1 and 4F2hc-LAT2, and their light chains LAT1 and LAT2. For this purpose, the HATs and the light chai...