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© The Rockefeller University Press, 0021-9525/2002/9/1155-a $5.00
The Journal of Cell Biology, Volume 158, Number 7, September 30, 2002 1155-a-1155

Stand up and take hold

Integrin affinity for extracellular ligands increases when it opens from a bent (left) to an extended (right) shape. Springer/Elsevier

Integrin is being examined inside and out. Olga Vinogradaova, Edward Plow, Jun Qin, and colleagues (The Cleveland Clinic Foundation, Cleveland, OH) have focused on its intracellular portion, and Junichi Takagi, Timothy Springer, and colleagues (Harvard Medical School, Boston, MA) have examined extracellular domains. Their combined efforts reveal a jackknife-like opening of the stimulated protein.

Changes in integrin structure in response to cellular signals regulate its binding to extracellular matrix (ECM) proteins like fibrinogen during processes such as platelet aggregation. Integrin is composed of and ß subunits, each of which is a transmembrane protein with a short cytoplasmic tail and several large extracellular domains. The binding sites for extracellular ligands lie far from the transmembrane domain, so how an intracellular signal is transmitted through so many extracellular domains has been difficult to determine.

The Cleveland Clinic group examined how the cytoplasmic tails respond to internal signals. Their studies revealed that the and ß tails of inactive integrin interact at a region adjacent to the plasma membrane. Activation of integrin, either by known constitutive mutations or by binding of the cytoskeletal protein talin, disrupted the cytoplasmic interaction and allowed the extracellular portion to bind fibrinogen.

The extracellular structural consequences of cytoplasmic uncoupling was then examined by the Harvard group. Their electron micrographs of linked soluble extracellular and ß domains confirmed a previous crystal structure of integrin in a condensed shape, like a "V" that points back toward the cell. A cell surface version held in this bent conformation by a disulfide bond did not bind fibrinogen unless the disulfide was broken. Based on the EM of the soluble protein, disrupting a membrane-proximal link between integrins causes the integrin to extend upwards like an opening switchblade. The extended form places the ligand-binding domain atop the dimer, where it is more accessible to physiological substrates. Thus, says Takagi, "we show that extension is at least partly responsible for making integrin high affinity." However, two extended forms were found, which differed in the angle of the ligand-binding region. Takagi is now examining how these two conformers affect ligand binding.

References:

Vinogradova, O., et al. 2002. Cell. 110:587–597.[CrossRef][Medline]

Takagi, J., et al. 2002. Cell. 110:599–611.[CrossRef][Medline]

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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This Article Full Text (PDF, 249K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Social Bookmarking                            What's this?