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WATERS/MACMILLAN
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Growth hormone activates its dimeric receptor (the growth hormone receptor ) by rotating one subunit relative to the other, according to Richard Brown, Michael Waters (University of Queensland, Australia), and colleagues.
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- [" x7 S& B2 W2 O4 m+ t5 R( X"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.
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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.
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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.
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Reference:
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Brown, R.J., et al. 2005. Nat. Struct. Mol. Biol. doi:10.1038/nsmb977.(Receptor rotation aligns activating kina) |
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发表于 2009-3-6 09:03
发表于 2026-10-23 13:08
