Cell
Volume 167, Issue 4, 3 November 2016, Pages 1041-1051.e11
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Article
Crystal Structure of a Full-Length Human Tetraspanin Reveals a Cholesterol-Binding Pocket

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Highlights

  • The structure of full-length CD81 reveals a cone-like architecture

  • A large intramembrane cavity exists within the transmembrane region

  • Cholesterol binds CD81 within the intramembrane cavity

  • MD simulations suggest that CD81 can adopt open and closed conformations

Summary

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

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

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