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Turning on by turning

Receptor rotation aligns activating kinases. WATERS/MACMILLAN

Growth hormone activates its dimeric receptor (the growth hormone receptor [GHR]) by rotating one subunit relative to the other, according to Richard Brown, Michael Waters (University of Queensland, Australia), and colleagues.

"The majority of textbooks today still say that cytokine receptor activation is by dimerization," says Brown. Brown and colleagues add to the accumulating evidence that unbound, inactive receptor is already dimeric by showing that the transmembrane and juxtamembrane domains hold the dimer together in the absence of ligand.

How else might receptor activation work? Another member of the cytokine receptor family, the erythropoietin receptor (EPOR), is thought to be activated by a scissor-like mechanism. The extracellular domains would keep the active faces of the intracellular domains far from each other until ligand binding allows the scissors to close. But when Brown and colleagues crystallized extracellular domains of the dimeric GHR with no ligand bound, they found that it differs little from the published structure that contains ligand.

Studies with EPOR are also consistent with some degree of activation by rotation, but the mechanism is unclear. The Brisbane group find that rotation—achieved by inserting alanines within the transmembrane domain -helix—can activate GHR. Insertion of four, but not fewer or more, alanines resulted in constitutive activation. Growth hormone apparently achieves the rotation because the two sites for binding GHR are placed asymmetrically. Rotation of transmembrane domains would align cytoplasmic JAK2 kinases so that they can transphosphorylate.

Reference:

Brown, R.J., et al. 2005. Nat. Struct. Mol. Biol. doi:10.1038/nsmb977.

William A. Wells

wellsw{at}rockefeller.edu

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This Article Full Text (PDF, 351K) 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 Wells, W. A. Search for Related Content PubMed Articles by Wells, W. A. Social Bookmarking                            What's this?