Advances on the Transfer of Lipids by Lipid Transfer Proteins

Wong, Louise H.; Čopič, Alenka; Levine, Tim P.

doi:10.1016/j.tibs.2017.05.001

Cited by 175 publications

(165 citation statements)

References 122 publications

(185 reference statements)

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“…Our earlier demonstration [10] that STARD10 is the likely causal gene at the T2D risk locus on chromosome 11q13 has emphasised the probable importance of lipid transfer for the normal physiology of the pancreatic β-cell. Indeed, the role of lipid transfer proteins has emerged recently as an important element in cell biology [42].…”

Section: Discussionmentioning

confidence: 99%

The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis

Carrat

Haythorne

Tomás

et al. 2020

Preprint

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AbstractObjectiveRisk alleles for type 2 diabetes at the STARD10 locus are associated with lowered STARD10 expression in the β-cell, impaired glucose-induced insulin secretion and decreased circulating proinsulin:insulin ratios. Although likely to serve as a mediator of intracellular lipid transfer, the identity of the transported lipids, and thus the pathways through which STARD10 regulates β-cell function, are not understood. The aim of this study was to identify the lipids transported and affected by STARD10 in the β-cell and its effect on proinsulin processing and insulin granule biogenesis and maturation.MethodsWe used isolated islets from mice deleted selectively in the β-cell for Stard10 (βStarD10KO) and performed electron microscopy, pulse-chase, RNA sequencing and lipidomic analyses. Proteomic analysis of STARD10 binding partners was executed in INS1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay were performed on purified STARD10 protein.ResultsβStarD10KO islets had a sharply altered dense core granule appearance, with a dramatic increase in the number of “rod-like” dense cores. Correspondingly, basal secretion of proinsulin was increased. Amongst the differentially expressed genes in βStarD10KO islets, expression of the phosphoinositide binding proteins Pirt and Synaptotagmin 1 were decreased while lipidomic analysis demonstrated changes in phosphatidyl inositol levels. The inositol lipid kinase PIP4K2C was also identified as a STARD10 binding partner. STARD10 bound to inositides phosphorylated at the 3’ position and solution of the crystal structure of STARD10 to 2.3 Å resolution revealed a binding pocket capable of accommodating polyphosphoinositides.ConclusionOur data indicate that STARD10 binds to, and may transport, phosphatidylinositides, influencing membrane lipid composition, insulin granule biosynthesis and insulin processing.

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Section: Discussionmentioning

confidence: 99%

The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis

Carrat

Haythorne

Tomás

et al. 2020

Preprint

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“…Protein-membrane interactions play pivotal roles in numerous biological processes, including membrane protein folding (Yu et al, 2017;Popot and Engelman, 2016;Min et al, 2015), lipid metabolism and transport (Giordano et al, 2013;Reinisch and De Camilli, 2016;Hammond and Balla, 2015;Wong et al, 2017), membrane trafficking (Zhou et al, 2017;Pérez-Lara et al, 2016;Wu et al, 2017;Hurley, 2006;Shen et al, 2012;McMahon and Gallop, 2005), signal transduction (Dong et al, 2017;Aggarwal and Ha, 2016;Lemmon, 2008;Das et al, 2015), and cell motility (Wang and Ha, 2013;Tsujita and Itoh, 2015). Studying these interactions is often difficult, especially when they involve multiple intermediates, multiple ligands, mechanical force, large energy changes, or protein aggregation (Dong et al, 2017;Pérez-Lara et al, 2016;Arauz et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Single-molecule force spectroscopy of protein-membrane interactions

Cai

et al. 2017

Preprint

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Many biological processes rely on protein-membrane interactions in the presence of mechanical forces, yet high resolution methods to quantify such interactions are lacking. Here, we describe a single-molecule force spectroscopy approach to quantify membrane binding of C2 domains in Synaptotagmin-1 (Syt1) and Extended Synaptotagmin-2 (E-Syt2). Syts and E-Syts bind the plasma membrane via multiple C2 domains, bridging the plasma membrane with synaptic vesicles or endoplasmic reticulum to regulate membrane fusion or lipid exchange, respectively. In our approach, single proteins attached to membranes supported on silica beads are pulled by optical tweezers, allowing membrane binding and unbinding transitions to be measured with unprecedented spatiotemporal resolution. C2 domains from either protein resisted unbinding forces of 2-7 pN and had binding energies of 4-14 k B T per C2 domain. Regulation by bilayer composition or Ca 2+ recapitulated known properties of both proteins. The method can be widely applied to study protein-membrane interactions.

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“…Because lipids are insoluble in water, during nonvesicular transport, they are shielded from the water-rich cytoplasm by proteins that hold them in an internal hydrophobic pocket. Such lipid transfer proteins (LTPs) often act in regions in which one organelle comes~30 nm away from another membrane, the so-called MCSs (Wong, Copic, & Levine, 2017). Plants induce LTPs' expression and secretion as a defence mechanism against pathogens (Kushwaha, Singh, Basu, & Chakraborty, 2015;Ooi et al, 2008;Park et al, 2002;Sohal, Pallas, & Jenkins, 1999).…”

Section: Interfering With Lipid Trafficking At Membrane Contact Sitesmentioning

confidence: 99%

Targeting host lipid flows: Exploring new antiviral and antibiotic strategies

Fernández-Oliva

Ortega-González

Risco

2019

Cellular Microbiology

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Bacteria and viruses pose serious challenges for humans because they evolve continuously. Despite ongoing efforts, antiviral drugs to treat many of the most troubling viruses have not been approved yet. The recent launch of new antimicrobials is generating hope as more and more pathogens around the world become resistant to available drugs. But extra effort is still needed. One of the current strategies for antiviral and antibiotic drug development is the search for host cellular pathways used by many different pathogens. For example, many viruses and bacteria alter lipid synthesis and transport to build their own organelles inside infected cells. The characterization of these interactions will be fundamental to identify new targets for antiviral and antibiotic drug development. This review discusses how viruses and bacteria subvert cell machineries for lipid synthesis and transport and summarises the most promising compounds that interfere with these pathways.

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Advances on the Transfer of Lipids by Lipid Transfer Proteins

Cited by 175 publications

References 122 publications

The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis

The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis

Single-molecule force spectroscopy of protein-membrane interactions

Targeting host lipid flows: Exploring new antiviral and antibiotic strategies

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