Scientists Report Cryo-EM Structure of a Human Platelet
Integrin Molecule
By Jason Socrates
Bardi
Two researchers at The Scripps Research Institute (TSRI)
recently published the first detailed three-dimensional model
for the human platelet integrin alphaIIbbeta3—a
signaling molecule that is important for activating platelets,
which leads to the healthy formation of blood clots in response
to a cut as well as clots that obstruct blood flow to healthy
tissue.
The structure, which was obtained through electron cryo-microscopy
(cryo-EM), image analysis, and molecular modeling, will appear
in this week's issue of the journal Proceedings of the
National Academy of the Sciences and reveals new structural
details of this important molecule.
These results will be relevant for the design of new drugs
to treat health conditions in which the formation of blood
clots is undesirable, such as during myocardial infarctions
(heart attacks) and strokes. Medical techniques like balloon
angioplasty and intracoronary stent implantation are designed
to clear blocked arteries but can also cause the formation
of thrombi. In fact, several recent clinical trials have demonstrated
that alphaIIbbeta3 inhibitors have benefit
in the medical treatment not only for heart attacks but also
during angioplasty and stent placement.
The Structure Revealed
Picture an integrin as a large button on an overcoat. Most
of it sits exposed on the outside of the coat, but it is connected
by threads that extend to the inside of the material.
Actually, the integrin is something of a scientific marvel
because it transduces signals over a distance of nearly 200
Ångstroms, whereas most signaling molecules work over
a distance of 10 to 15 Ångstroms. Integrins are made
up of two separate polypeptide chains (called the alpha and
beta chains) that come in a variety of forms. Recent crystallographic
studies by the Arnaout group at Harvard revealed that the
large extracellular portion of the molecule, the "button,"
has 12 distinct folding "domains."
"Integrins have a large and very complicated structure,"
says Mark Yeager, M.D., Ph.D., who published this latest integrin
structure with his postdoctoral fellow Brian Adair, Ph.D.
"They are a broad class of signaling molecules that affect
diverse biological processes such as development, angiogenesis,
wound healing, neoplastic transformation, and thrombosis."
The integrin alphaIIbbeta3
is particularly important in the process that leads to thrombosis
because it is one of the key signaling molecules on platelets,
the disk-shaped cells that are involved in blood clotting.
There are typically 40,000 to 80,000 on the surface of any
given platelet, spanning the platelet membranes, where they
are involved in signal transduction—detecting specific
molecules (ligands) outside the cell and communicating that
detection to the inside, or vice-versa. The ligands are proteins
attached to other cells, in the extracellular matrix, or that
freely circulate in the bloodstream.
When these ligand molecules bind to the extracellular integrin
subunits, they induce "outside-in" signaling in which a three-dimensional
conformational change at one end of the integrin is propagated
through the membrane to the other end of the integrin. Thus,
the binding event on one side of the cell is "transduced"
through the cellular membrane. Proteins inside cells can also
bind to the cytoplasmic "threads" of the integrins and alter
the extracellular affinity for ligands, a process termed "inside-out"
signaling.
According to the model that Adair and Yeager now propose,
the alphaIIbbeta3 integrins have multiple
conformations and undergo dramatic shape changes depending
on whether the molecule is in the high- or low-affinity state.
The "threads" that transmit the signal through the membrane
are folded as a coiled-coil of alpha-helices.
When the platelet is activated, the integrin is in a "high-affinity"
form, extending far out on the outside of the cell and exposing
its binding site to potential ligands. One of the ligands
that binds to the high-affinity conformation is fibrinogen,
a circulating blood protein that can bind integrins at both
ends. Fibrinogen is present in large amounts in the blood,
and when platelets are active, the high-affinity integrins
bind to fibrinogen proteins, which in turn bind more integrins
at their other end, and this leads to the formation of massive
clots of platelets.
"We hypothesize that the switch between the high- and low-affinity
states for the integrin involves flexing at hinge-like connections
between certain domains in the extracellular subunits so that
the molecule collapses into a tighter overall structure,"
says Yeager. "It is a very dramatic event."
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Brian Adair (left) and Mark Yeager are
publishing an integrin structure in the journal
Proceedings of the National Academy of the Sciences.
Photo by Jason S. Bardi.
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