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Establishing the mechanistic basis of sugar transport
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0001-7104-6442
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Sugar is a vital molecule required for cell viability and homeostasis. Sugar is important for metabolic energy, energy storage, signaling, structure and osmolyte regulation. Transport of sugar represents an important physiological process. Specific membrane transporter families have evolved to mediate the transport of sugar across biological membranes. In this thesis, we describe our work leading to a better mechanistic understanding of two sugar transporter families, namely glucose (GLUT) transporters and nucleotide-sugar (NST) transporters.

Members of GLUT transporters, belonging to the Solute Carrier (SLC2) family, are involved in the uptake of various monosaccharides across the cellular membranes. Activity of different NSTs, belonging to the (SLC35) family, is crucial for the process of glycosylation by mediating the translocation of activated sugars from the cytoplasm into the lumen of either Golgi and/or ER organelles. GLUTs and NSTs families carry out transport processes fundamental to human physiology and pathophysiology. Despite the profound importance of GLUTs and NSTs in human health, comprehensive understanding of their architecture and mechanistic features with respect to determinants of substrate binding and allosteric coupling at the molecular level has remained elusive.

In this thesis, we address key functional and structural properties of GLUT and NST mediated sugar transport. We combine crystal structures with robust binding and transport assays as well as computational approaches. The role of lipids in fine-tuning the activity of transporters is also exemplified by demonstrating the effect of lipid composition in the transport activity of GLUTs using in-vitro proteoliposome assays. Our work has not only enhanced the current understanding of GLUT and NST function, but also developed themes and methods that are likely relevant to many types of small molecule transporters.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University , 2019. , p. 58
Keywords [en]
membrane transport, transport energetics, nucleotide-sugar transporters, glucose transporters, malaria, cancer
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-175422ISBN: 978-91-7797-897-8 (print)ISBN: 978-91-7797-898-5 (electronic)OAI: oai:DiVA.org:su-175422DiVA, id: diva2:1365897
Public defence
2019-12-11, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Manuscript.

Available from: 2019-11-18 Created: 2019-10-25 Last updated: 2019-11-08Bibliographically approved
List of papers
1. Structure and mechanism of the mammalian fructose transporter GLUT5
Open this publication in new window or tab >>Structure and mechanism of the mammalian fructose transporter GLUT5
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2015 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 526, no 7573, p. 397-+Article in journal (Refereed) Published
Abstract [en]

The altered activity of the fructose transporter GLUT5, an isoform of the facilitated-diffusion glucose transporter family, has been linked to disorders such as type 2 diabetes and obesity. GLUT5 is also overexpressed in certain tumour cells, and inhibitors are potential drugs for these conditions. Here we describe the crystal structures of GLUT5 from Rattus norvegicus and Bos taurus in open outward-and open inward-facing conformations, respectively. GLUT5 has a major facilitator superfamily fold like other homologous monosaccharide transporters. On the basis of a comparison of the inward-facing structures of GLUT5 and human GLUT1, a ubiquitous glucose transporter, we show that a single point mutation is enough to switch the substrate-binding preference of GLUT5 from fructose to glucose. A comparison of the substrate-free structures of GLUT5 with occluded substrate-bound structures of Escherichia coli XylE suggests that, in addition to global rocker-switch-like re-orientation of the bundles, local asymmetric rearrangements of carboxy-terminal transmembrane bundle helices TM7 and TM10 underlie a 'gated-pore' transport mechanism in such monosaccharide transporters.

National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-122925 (URN)10.1038/nature14909 (DOI)000362730200044 ()
Available from: 2015-11-16 Created: 2015-11-11 Last updated: 2019-11-01Bibliographically approved
2. Malarial parasite transporter structure reveals the molecular basis for sugar import
Open this publication in new window or tab >>Malarial parasite transporter structure reveals the molecular basis for sugar import
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(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-175418 (URN)
Available from: 2019-10-25 Created: 2019-10-25 Last updated: 2019-11-01Bibliographically approved
3. Lipids shape the flat energetic landscape of the GLUT transporter cycle
Open this publication in new window or tab >>Lipids shape the flat energetic landscape of the GLUT transporter cycle
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(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-175419 (URN)
Available from: 2019-10-25 Created: 2019-10-25 Last updated: 2019-11-01Bibliographically approved
4. Structural basis for the delivery of activated sialic acid into Golgi for sialyation
Open this publication in new window or tab >>Structural basis for the delivery of activated sialic acid into Golgi for sialyation
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2019 (English)In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 26, no 6, p. 415-423Article in journal (Refereed) Published
Abstract [en]

The decoration of secretory glycoproteins and glycolipids with sialic acid is critical to many physiological and pathological processes. Sialyation is dependent on a continuous supply of sialic acid into Golgi organelles in the form of CMP-sialic acid. Translocation of CMP-sialic acid into Golgi is carried out by the CMP-sialic acid transporter (CST). Mutations in human CST are linked to glycosylation disorders, and CST is important for glycopathway engineering, as it is critical for sialyation efficiency of therapeutic glycoproteins. The mechanism of how CMP-sialic acid is recognized and translocated across Golgi membranes in exchange for CMP is poorly understood. Here we have determined the crystal structure of a Zea mays CST in complex with CMP. We conclude that the specificity of CST for CMP-sialic acid is established by the recognition of the nucleotide CMP to such an extent that they are mechanistically capable of both passive and coupled antiporter activity.

National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-170105 (URN)10.1038/s41594-019-0225-y (DOI)000470110200006 ()31133698 (PubMedID)
Available from: 2019-07-02 Created: 2019-07-02 Last updated: 2019-11-01Bibliographically approved

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