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Structural basis for the delivery of activated sialic acid into Golgi for sialyation
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0001-6991-1046
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0003-0960-994X
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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Number of Authors: 52019 (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.

Place, publisher, year, edition, pages
2019. Vol. 26, no 6, p. 415-423
National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-170105DOI: 10.1038/s41594-019-0225-yISI: 000470110200006PubMedID: 31133698OAI: oai:DiVA.org:su-170105DiVA, id: diva2:1334420
Available from: 2019-07-02 Created: 2019-07-02 Last updated: 2019-11-01Bibliographically approved
In thesis
1. Establishing the mechanistic basis of sugar transport
Open this publication in new window or tab >>Establishing the mechanistic basis of sugar transport
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
membrane transport, transport energetics, nucleotide-sugar transporters, glucose transporters, malaria, cancer
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-175422 (URN)978-91-7797-897-8 (ISBN)978-91-7797-898-5 (ISBN)
Public defence
2019-12-11, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
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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

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