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Cell. 2016 Nov 3;167(4):1041-1051.e11. doi: 10.1016/j.cell.2016.09.056. Epub 2016 Oct 27.

Crystal Structure of a Full-Length Human Tetraspanin Reveals a Cholesterol-Binding Pocket.

Author information

1
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
2
Departments of Computer Science and of Molecular and Cellular Physiology and Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA.
3
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: andrew_kruse@hms.harvard.edu.
4
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: stephen_blacklow@hms.harvard.edu.

Abstract

Tetraspanins comprise a diverse family of four-pass transmembrane proteins that play critical roles in the immune, reproductive, genitourinary, and auditory systems. Despite their pervasive roles in human physiology, little is known about the structure of tetraspanins or the molecular mechanisms underlying their various functions. Here, we report the crystal structure of human CD81, a full-length tetraspanin. The transmembrane segments of CD81 pack as two largely separated pairs of helices, capped by the large extracellular loop (EC2) at the outer membrane leaflet. The two pairs of helices converge at the inner leaflet to create an intramembrane pocket with additional electron density corresponding to a bound cholesterol molecule within the cavity. Molecular dynamics simulations identify an additional conformation in which EC2 separates substantially from the transmembrane domain. Cholesterol binding appears to modulate CD81 activity in cells, suggesting a potential mechanism for regulation of tetraspanin function.

KEYWORDS:

CD19; CD81; X-ray crystallography; membrane protein; protein structure; protein trafficking

PMID:
27881302
PMCID:
PMC5127602
DOI:
10.1016/j.cell.2016.09.056
[Indexed for MEDLINE]
Free PMC Article

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