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CSUMECH SIGNED

Cholesterol and Sugar Uptake Mechanisms

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EC-Contrib. €

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Project "CSUMECH" data sheet

The following table provides information about the project.

Coordinator
AARHUS UNIVERSITET 

Organization address
address: NORDRE RINGGADE 1
city: AARHUS C
postcode: 8000
website: www.au.dk

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Denmark [DK]
 Total cost 1˙499˙848 €
 EC max contribution 1˙499˙848 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2014-STG
 Funding Scheme ERC-STG
 Starting year 2015
 Duration (year-month-day) from 2015-07-01   to  2020-06-30

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    AARHUS UNIVERSITET DK (AARHUS C) coordinator 1˙499˙848.00

Map

 Project objective

Cardiovascular disease, diabetes and cancer have a dramatic impact on modern society, and in great part are related to uptake of cholesterol and sugar. We still know surprisingly little about the molecular details of the processes that goes on in this essential part of human basic metabolism. This application addresses cholesterol and sugar transport and aim to elucidate the molecular mechanism of cholesterol and sugar uptake in humans. It moves the frontiers of the field by shifting the focus to in vitro work allowing hitherto untried structural and biochemical experiments to be performed. Cholesterol uptake from the intestine is mediated by the membrane protein NPC1L1. Despite extensive research, the molecular mechanism of NPC1L1-dependent cholesterol uptake still remains largely unknown. Facilitated sugar transport in humans is made possible by sugar transporters called GLUTs and SWEETs, and every cell possesses these sugar transport systems. For all these uptake systems structural information is sorely lacking to address important mechanistic questions to help elucidate their molecular mechanism. I will address this using a complementary set of methods founded in macromolecular crystallography and electron microscopy to determine the 3-dimensional structures of key players in these uptake systems. My unpublished preliminary results have established the feasibility of this approach. This will be followed up by biochemical characterization of the molecular mechanism in vitro and in silico. This high risk/high reward membrane protein proposal could lead to a breakthrough in how we approach human biochemical pathways that are linked to trans-membrane transport. An improved understanding of cholesterol and sugar homeostasis has tremendous potential for improving general public health, and furthermore this proposal will help to uncover general principles of endocytotic uptake and facilitated diffusion systems at the molecular level.

 Publications

year authors and title journal last update
List of publications.
2019 Bjørn P. Pedersen, David L. Stokes, Hans-Jürgen Apell
The KdpFABC complex – K + transport against all odds
published pages: 1-34, ISSN: 0968-7688, DOI: 10.1080/09687688.2019.1638977
Molecular Membrane Biology 2020-03-05
2019 Peter Aasted Paulsen, Tânia F. Custódio, Bjørn Panyella Pedersen
Crystal structure of the plant symporter STP10 illuminates sugar uptake mechanism in monosaccharide transporter superfamily
published pages: , ISSN: 2041-1723, DOI: 10.1038/s41467-018-08176-9
Nature Communications 10/1 2020-03-05
2019 Mikael B.L. Winkler, Rune T. Kidmose, Maria Szomek, Katja Thaysen, Shaun Rawson, Stephen P. Muench, Daniel Wüstner, Bjørn Panyella Pedersen
Structural Insight into Eukaryotic Sterol Transport through Niemann-Pick Type C Proteins
published pages: 485-497.e18, ISSN: 0092-8674, DOI: 10.1016/j.cell.2019.08.038
Cell 179/2 2020-03-05
2019 Rune Thomas Kidmose, Jonathan Juhl, Poul Nissen, Thomas Boesen, Jesper Lykkegaard Karlsen, Bjørn Panyella Pedersen
Namdinator – automatic molecular dynamics flexible fitting of structural models into cryo-EM and crystallography experimental maps
published pages: 526-531, ISSN: 2052-2525, DOI: 10.1107/s2052252519007619
IUCrJ 6/4 2020-03-05
2017 Ching-Shin Huang, Bjørn Panyella Pedersen, David L. Stokes
Crystal structure of the potassium-importing KdpFABC membrane complex
published pages: 681-685, ISSN: 0028-0836, DOI: 10.1038/nature22970
Nature 546/7660 2019-05-28
2016 Khyati Kapoor, Janet S. Finer-Moore, Bjørn P. Pedersen, Laura Caboni, Andrew Waight, Roman C. Hillig, Peter Bringmann, Iring Heisler, Thomas Müller, Holger Siebeneicher, and Robert M. Stroud
Mechanism of inhibition of human glucose transporter GLUT1 is conserved between cytochalasin B and phenylalanine amides
published pages: , ISSN: 1091-6490, DOI: 10.1073/pnas.1603735113
Proc Natl Acad Sci U S A 2019-05-24
2016 Pedersen BP, Gourdon P, Liu X, Karlsen JL, Nissen P.
Initiating heavy-atom-based phasing by multi-dimensional molecular replacement.
published pages: , ISSN: 2059-7983, DOI: 10.1107/S2059798315022482
Acta Crystallogr D Struct Biol. 2019-05-24
2016 Lyons JA, Shahsavar A, Paulsen PA, Pedersen BP, Nissen P.
Expression strategies for structural studies of eukaryotic membrane proteins.
published pages: , ISSN: 0959-440X, DOI: 10.1016/j.sbi.2016.06.011
Curr Opin Struct Biol. 2019-05-24

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