Tight junctions contain oligomeric protein assembly critical for maintaining blood-brain barrier integrity in vivo.

Gwen McCaffrey, William D. Staatz, Carolyn A. Quigley, Nicole Nametz, Melissa J. Seelbach, Chris R. Campos, Tracy A. Brooks, Richard D. Egleton, Thomas P Davis

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Tight junctions (TJs) are major components of the blood-brain barrier (BBB) that physically obstruct the interendothelial space and restrict paracellular diffusion of blood-borne substances from the peripheral circulation to the CNS. TJs are dynamic structures whose intricate arrangement of oligomeric transmembrane and accessory proteins rapidly alters in response to external stressors to produce changes in BBB permeability. In this study, we investigate the constitutive trafficking of the TJ transmembrane proteins occludin and claudin-5 that are essential for forming the TJ seal between microvascular endothelial cells that inhibits paracellular diffusion. Using a novel, detergent-free OptiPrep density-gradient method to fractionate rat cerebral microvessels, we identify a plasma membrane lipid raft domain that contains oligomeric occludin and claudin-5. Our data suggest that oligomerization of occludin involves disulfide bond formation within transmembrane regions, and that assembly of the TJ oligomeric protein complex is facilitated by an oligomeric caveolin scaffold. This is the first time that distribution of oligomeric TJ transmembrane proteins within plasma membrane lipid rafts at the BBB has been examined in vivo. The findings reported in this study are critical to understand the mechanism of assembly of the TJ multiprotein complex that is essential for maintaining BBB integrity.

Original languageEnglish (US)
Pages (from-to)2540-2555
Number of pages16
JournalJournal of Neurochemistry
Volume103
Issue number6
DOIs
StatePublished - Dec 2007
Externally publishedYes

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Tight Junctions
Occludin
Tight Junction Proteins
Blood-Brain Barrier
Claudin-5
Cell membranes
Membrane Lipids
Proteins
Cell Membrane
Caveolins
Multiprotein Complexes
Oligomerization
Gradient methods
Endothelial cells
Accessories
Microvessels
Scaffolds
Disulfides
Detergents
Seals

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Tight junctions contain oligomeric protein assembly critical for maintaining blood-brain barrier integrity in vivo. / McCaffrey, Gwen; Staatz, William D.; Quigley, Carolyn A.; Nametz, Nicole; Seelbach, Melissa J.; Campos, Chris R.; Brooks, Tracy A.; Egleton, Richard D.; Davis, Thomas P.

In: Journal of Neurochemistry, Vol. 103, No. 6, 12.2007, p. 2540-2555.

Research output: Contribution to journalArticle

McCaffrey, G, Staatz, WD, Quigley, CA, Nametz, N, Seelbach, MJ, Campos, CR, Brooks, TA, Egleton, RD & Davis, TP 2007, 'Tight junctions contain oligomeric protein assembly critical for maintaining blood-brain barrier integrity in vivo.', Journal of Neurochemistry, vol. 103, no. 6, pp. 2540-2555. https://doi.org/10.1111/j.1471-4159.2007.05120.x
McCaffrey, Gwen ; Staatz, William D. ; Quigley, Carolyn A. ; Nametz, Nicole ; Seelbach, Melissa J. ; Campos, Chris R. ; Brooks, Tracy A. ; Egleton, Richard D. ; Davis, Thomas P. / Tight junctions contain oligomeric protein assembly critical for maintaining blood-brain barrier integrity in vivo. In: Journal of Neurochemistry. 2007 ; Vol. 103, No. 6. pp. 2540-2555.
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