title: How serpins transport hormones and regulate their release.
abstract: The adaptation of the serpin framework and its mechanism to perform diverse functions is epitomised in the hormone carriers of the blood. Thyroxine and the corticosteroids are transported bound in a 1:1 ratio on almost identical sites in the two homologous binding-globulins, TBG and CBG. Recent structural findings show an equilibrated, rather than on-and-off, release of the hormones from the carriers, reflecting small reversible movements of the hinge region of the reactive loop that modify the conformational flexibility of the underlying hormone-binding site. Consequently, contrary to previous concepts, the binding affinities of TBG and CBG are not fixed but can be allosterically modified to allow differential hormone delivery. Notably, the two carriers function like protein thermocouples with a surge in hormone release as body temperatures rise in fevers, and conversely a large diminution in free hormone levels at hibernation temperatures. By comparison angiotensinogen, the source of the angiotensin peptides that control blood pressure, does not appear to utilise the serpin mechanism. It has instead evolved a 63 residue terminal extension containing the buried angiotensin cleavage site, which on interaction moves into the active cleft of the renin. The conformational shift involved is critically linked by a labile disulphide bridge. The observation of changes in the redox status of this S-S bridge, in the hypertensive complication of pregnancy, pre-eclampsia, has opened an unexpected level of regulation at what is the initial stage in the control of blood pressure.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. Electronic address: rwc1000@cam.ac.uk.
authors.forename: Robin W
authors.initials: RW
authors.lastname: Carrell
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Read
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001692:Biological Transport; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015843:Serpins / Q000378:metabolism*
chemical_list: D006728:Hormones; D015843:Serpins
keywords: Angiotensin; Angiotensinogen; CBG; Cortisol; TBG; Thyroxine