| 1. |
- de Maré, Sofia W., et al.
(författare)
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Structural Basis for Glycerol Efflux and Selectivity of Human Aquaporin 7
- 2020
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Ingår i: Structure. - : Elsevier BV. - 0969-2126. ; 28:2, s. 3-222
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Tidskriftsartikel (refereegranskat)abstract
- AQP7 is an important glycerol channel in human adipocytes, and its dysfunction is linked to metabolic disorders. The high-resolution X-ray structures of AQP7 unravels the molecular details of how glycerol travels through the channel and provide a structural basis for development of small-molecule drugs for targeting AQP7.
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| 2. |
- de Mare, Sofia
(författare)
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Regulation of glycerol efflux in adipocytes. Structural and functional studies of the glycerol channel aquaporin 7.
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Glycerol levels in adipocytes depend on the lipolysis, the hydrolysis of triglycerides into glycerol and free fatty acids, and the efflux of glycerol across the plasma membrane through glycerol channels. The aims of this work were to investigate how glycerol levels are regulated on a molecular level by PLIN1, a major lipid droplet-associated protein and a key regulator of the lipolysis by scaffolding for lipolytic proteins on the lipid droplet. Furthermore to elucidate the selectivity and conducting mechanisms of aquaporin 7 (AQP7), the major glycerol channel in adipocytes.PLIN1 was found to form micro domains in human primary adipocytes during basal conditions, and the micro domains dispersed after lipolytic stimulation. Interactions specifically with cholesteryl esters, DPPC and triglycerides on the lipid droplet formed the basis for the dynamic PLIN1 micro domains. The dispersion of PLIN1 along with bound lipolytic proteins results in a fully activated lipolysis. Further, PLIN1 was identified as an interacting partner to AQP7. Protein kinase A phosphorylation of the AQP7 N-terminus decreased the binding to PLIN1, resulting in translocation from the lipid droplet to the plasma membrane for glycerol efflux. The high-resolution crystal structure of AQP7 was determined with glycerol and water molecules lining the channel. A conducting mechanism was proposed in which the glycerol partly rotates as it travels along the pore, possibly facilitating the transition by altering the hydrogen bond network and releasing the glycerol from more tightly bound positions. Moreover, molecular dynamics simulations suggested that glycerol hinders water from diffusing through the pore at a high rate. Initial crystal growth of AQP7 for neutron diffraction studies was carried out, in order to be able to precisely locate hydrogen atoms and gain a deeper understanding of the selectivity and conducting mechanisms.Glycerol metabolism has implications in metabolic diseases and AQP7-knockout mice develop obesity and type 2 diabetes. This research has deepened our knowledge of how glycerol levels in adipocytes are regulated by PLIN1. Adipocyte lipolysis is upregulated by certain cancers in order to supply energy for rapid tumor growth. The structure of AQP7 unraveled the details of glycerol efflux through AQP7 and provides a structural basis for development of small- molecules drugs targeting AQP7.
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| 3. |
- Hansen, Jesper S., et al.
(författare)
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Visualization of lipid directed dynamics of perilipin 1 in human primary adipocytes
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Perilipin 1 is a lipid droplet coating protein known to regulate lipid metabolism in adipocytes by serving as a physical barrier as well as a recruitment site for lipases to the lipid droplet. Phosphorylation of perilipin 1 by protein kinase A rapidly initiates lipolysis, but the detailed mechanism on how perilipin 1 controls lipolysis is unknown. Here, we identify specific lipid binding properties of perilipin 1 that regulate the dynamics of lipolysis in human primary adipocytes. Cellular imaging combined with biochemical and biophysical analyses demonstrate that perilipin 1 specifically binds to cholesteryl esters, and that their dynamic properties direct segregation of perilipin 1 into topologically distinct micro domains on the lipid droplet. Together, our data points to a simple unifying mechanism that lipid assembly and segregation control lipolysis in human primary adipocytes.
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| 4. |
- Huang, Peng, et al.
(författare)
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Cryo-EM structure supports a role of AQP7 as a junction protein
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Aquaglyceroporin 7 (AQP7) facilitates glycerol flux across the plasma membrane with a critical physiological role linked to metabolism, obesity, and associated diseases. Here, we present the single-particle cryo-EM structure of AQP7 determined at 2.55 Å resolution adopting two adhering tetramers, stabilized by extracellularly exposed loops, in a configuration like that of the well-characterized interaction of AQP0 tetramers. The central pore, in-between the four monomers, displays well-defined densities restricted by two leucine filters. Gas chromatography mass spectrometry (GC/MS) results show that the AQP7 sample contains glycerol 3-phosphate (Gro3P), which is compatible with the identified features in the central pore. AQP7 is shown to be highly expressed in human pancreatic α- and β- cells suggesting that the identified AQP7 octamer assembly, in addition to its function as glycerol channel, may serve as junction proteins within the endocrine pancreas.
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| 5. |
- Söndergaard Hansen, Jesper, et al.
(författare)
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Perilipin 1 binds to aquaporin 7 in human adipocytes and controls its mobility via protein kinase A mediated phosphorylation
- 2016
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Ingår i: Metabolism-Clinical and Experimental. - : Elsevier BV. - 0026-0495. ; 65:12, s. 1731-1742
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence suggests that dysregulated glycerol metabolism contributes to the pathophysiology of obesity and type 2 diabetes. Glycerol efflux from adipocytes is regulated by the aquaglyceroporin AQP7, which is translocated upon hormone stimulation. Here, we propose a molecular mechanism where the AQP7 mobility in adipocytes is dependent on perilipin 1 and protein kinase A. Biochemical analyses combined with ex vivo studies in human primary adipocytes, demonstrate that perilipin 1 binds to AQP7, and that catecholamine activated protein kinase A phosphorylates the N-terminus of AQP7, thereby reducing complex formation. Together, these findings are indicative of how glycerol release is controlled in adipocytes, and may pave the way for the future design of drugs against human metabolic pathologies.
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