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

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 und...

Full description

Saved in:
Bibliographic Details
Published in:Cell 2016-11, Vol.167 (4), p.1041-1051.e11
Main Authors: Zimmerman, Brandon, Kelly, Brendan, McMillan, Brian J., Seegar, Tom C.M., Dror, Ron O., Kruse, Andrew C., Blacklow, Stephen C.
Format: Article
Language:English
Subjects:
BASIC BIOLOGICAL SCIENCES
Binding Sites
CD19
CD81
Cholesterol - metabolism
Crystallography, X-Ray
Humans
membrane protein
Models, Chemical
Molecular Dynamics Simulation
protein structure
protein trafficking
Tetraspanin 28 - chemistry
Tetraspanin 28 - metabolism
X-ray crystallography
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
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. [Display omitted] •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 The tetraspanin CD81 contains a large intramembrane cavity occupied by cholesterol, indicating the potential for functional modulation by small molecules.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2016.09.056