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A switch that makes a blood clot sticky found within the platelet membrane

02.05.2003


One key to platelet integrin receptor found in transmembrane region



Integrin receptors allow cells to attach to other cells and to connective tissue which is necessary to form tissues, organs, or even people, for that matter. Researchers at the University of Pennsylvania School of Medicine have demonstrated that a key to activating αIIbβ3, the integrin that allows platelets to form blood clots, can be found in the part of the molecule embedded within a platelet’s outer membrane.

The αIIbβ3 integrin, also known as the platelet fibrinogen receptor or GP IIb-IIIa, has been the focus of an entire class of blood-thinning drugs, called GPIIb-IIIa agonists. The Penn researchers findings, published in this week’s issue of Science, have implications for drugs created to thin the blood and, perhaps more broadly, offer an intriguing hint as to how integrins on cells throughout the body may function.


"The part of the GPIIb-IIIa molecule that is embedded in the fatty layers that constitute the platelet’s outer membrane can determine whether or not the integrin is activated, thereby making the platelet ’sticky,’" said Joel S. Bennett, MD, Professor in Penn’s Division of Hematology/Oncology within the Department of Medicine. "The transmembrane region, which was generally assumed to be just an anchor for keeping the integrin receptor in place, can be an activating switch for the entire molecule."

Once activated, the two subunits of GPIIb-IIIa that extend outside the cell can clasp the walls of a damaged blood vessel or a passing fibrinogen molecule ¡V much like a bobby pin can close around strands of hair ¡V thereby forming a normal blood clot or a pathologic thrombus. GPIIb-IIIa agonist drugs, such as ReoPro®, Integrilin®, and Aggrastat®, work by preventing activated GPIIb-IIIa from binding to other objects in the bloodstream.

Since it is a protein, GPIIb-IIIa is made up of amino acids, strung along in a specific sequence to give the protein its shape. Bennett and his colleagues were able to determine which amino acids are responsible for activating GPIIb-IIIa by substituting a ’wrong’ amino acid at spaces along the  protein chain and expressing the mutant protein in cells growing in culture. They found that the transmembrane portion of one of the GPIIb-IIIa subunits is responsible for responding to activation signals and, in return, causing groups of the activated integrin to cluster.

"Remarkably, these regions are evolutionarily conserved ¡V meaning the transmembrane region in GPIIb-IIIa is the same in apes or rabbits or mice as they are in humans," said Bennett. "That tells us that the sequences of the transmembrane region of integrins are important factors in how these proteins function."

Moreover, nearly every integrin has a different transmembrane region made up of a unique amino acid sequence. If the transmembrane regions of all integrins work on a similar scheme, it would provide a new paradigm for the function of integrins and other cell membrane proteins.

"Integrin receptors are more than just a cellular form of Velcro ¡V as integrins bind, they can also generate signals that command a cell to act, such as whether to divide or differentiate or to produce an important protein such as a gene transcription factor," said Bennett. "It will be interesting, and even medically important, to determine how these signals can be modulated."

Other scientists involved in the research paper described here include Renhao Li, Neal Mitra, Holly Gratkowski, Gaston Vilaire, Reustem Litvinov, Chandrasekaran Nagasami, John Weisel, James D. Lear, and William F. DeGrado from Penn.

Greg Lester | EurekAlert!
Further information:
http://www.med.upenn.edu/

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