5mug

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Self-assembled alpha-Tocopherol Transfer Protein Nanoparticles Promote Vitamin E Delivery Across an Endothelial Barrier

Structural highlights

5mug is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.42Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TTPA_HUMAN Defects in TTPA are the cause of ataxia with isolated vitamin E deficiency (AVED) [MIM:277460. AVED is an autosomal recessive disease characterized by spinocerebellar degeneration. It causes ataxia and peripheral neuropathy that resembles Friedreich ataxia. AVED patients have markedly reduced plasma levels of vitamin E.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Function

TTPA_HUMAN Binds alpha-tocopherol and enhances its transfer between separate membranes.

Publication Abstract from PubMed

Vitamin E is one of the most important natural antioxidants, protecting polyunsaturated fatty acids in the membranes of cells. Among different chemical isoforms assimilated from dietary regimes, RRR-alpha-tocopherol is the only one retained in higher animals. This is possible thanks to alpha-Tocopherol Transfer Protein (alpha-TTP), which extracts alpha-tocopherol from endosomal compartments in liver cells, facilitating its distribution into the body. Here we show that, upon binding to its substrate, alpha-TTP acquires tendency to aggregation into thermodynamically stable high molecular weight oligomers. Determination of the structure of such aggregates by X-ray crystallography revealed a spheroidal particle formed by 24 protein monomers. Oligomerization is triggered by refolding of the N-terminus. Experiments with cultured cell monolayers demonstrate that the same oligomers are efficiently transported through an endothelial barrier (HUVEC) and not through an epithelial one (Caco-2). Discovery of a human endogenous transport protein with intrinsic capability of crossing endothelial tissues opens to new ways of drug delivery into the brain or other tissues protected by endothelial barriers.

Self-assembled alpha-Tocopherol Transfer Protein Nanoparticles Promote Vitamin E Delivery Across an Endothelial Barrier.,Aeschimann W, Staats S, Kammer S, Olieric N, Jeckelmann JM, Fotiadis D, Netscher T, Rimbach G, Cascella M, Stocker A Sci Rep. 2017 Jul 10;7(1):4970. doi: 10.1038/s41598-017-05148-9. PMID:28694484^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hentati A, Deng HX, Hung WY, Nayer M, Ahmed MS, He X, Tim R, Stumpf DA, Siddique T, Ahmed. Human alpha-tocopherol transfer protein: gene structure and mutations in familial vitamin E deficiency. Ann Neurol. 1996 Mar;39(3):295-300. PMID:8602747 doi:http://dx.doi.org/10.1002/ana.410390305
↑ Cavalier L, Ouahchi K, Kayden HJ, Di Donato S, Reutenauer L, Mandel JL, Koenig M. Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. Am J Hum Genet. 1998 Feb;62(2):301-10. PMID:9463307 doi:S0002-9297(07)63495-8
↑ Ouahchi K, Arita M, Kayden H, Hentati F, Ben Hamida M, Sokol R, Arai H, Inoue K, Mandel JL, Koenig M. Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet. 1995 Feb;9(2):141-5. PMID:7719340 doi:http://dx.doi.org/10.1038/ng0295-141
↑ Gotoda T, Arita M, Arai H, Inoue K, Yokota T, Fukuo Y, Yazaki Y, Yamada N. Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the alpha-tocopherol-transfer protein. N Engl J Med. 1995 Nov 16;333(20):1313-8. PMID:7566022
↑ Morley S, Panagabko C, Shineman D, Mani B, Stocker A, Atkinson J, Manor D. Molecular determinants of heritable vitamin E deficiency. Biochemistry. 2004 Apr 13;43(14):4143-9. PMID:15065857 doi:10.1021/bi0363073
↑ Mariotti C, Gellera C, Rimoldi M, Mineri R, Uziel G, Zorzi G, Pareyson D, Piccolo G, Gambi D, Piacentini S, Squitieri F, Capra R, Castellotti B, Di Donato S. Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families. Neurol Sci. 2004 Jul;25(3):130-7. PMID:15300460 doi:10.1007/s10072-004-0246-z
↑ Aeschimann W, Staats S, Kammer S, Olieric N, Jeckelmann JM, Fotiadis D, Netscher T, Rimbach G, Cascella M, Stocker A. Self-assembled alpha-Tocopherol Transfer Protein Nanoparticles Promote Vitamin E Delivery Across an Endothelial Barrier. Sci Rep. 2017 Jul 10;7(1):4970. doi: 10.1038/s41598-017-05148-9. PMID:28694484 doi:http://dx.doi.org/10.1038/s41598-017-05148-9