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.

Protease Inhibitors in Tick Saliva: The Role of Serpins and Cystatins in Tick-host-Pathogen Interaction

“…Angiotensinogen is a non-inhibitory serpin that is proteolytically activated by renin into several oligopeptides (angiotensins) that regulate vasoconstriction and blood pressure (Lu et al, 2016). Cortisol and thyroxine-binding proteins (human SERPINA6 and SERPINA7 ) are also notable serpins that act as major transport proteins for glucocorticoids and progesterone (Carrell and Read, 2016). Inhibitory serpins have very diverse functions depending on their specificity, but their importance is highlighted by the serpinopathies—diseases caused by serpin dysfunction or deficiency (Belorgey et al, 2007).…”

Human PZP and common marmoset A2ML1 as pregnancy related proteins

“…Serine protease inhibitor (SERPIN) family proteins include not only protease inhibitors but also regulators of coagulation or fibrinolysis, transporters of hormones, and suppressors of inflammation 38 . It is known that abnormalities of SERPIN are associated with preeclampsia, a condition in which abnormal blood vessels form in the placenta and become ischaemic.…”

Angiotensin-(1-7) and Mas receptor in the brain

“…Natalia L. Rukavina Mikusic * , Angélica M. Pineda, Mariela M. Gironacci Dpto. Quí� mica Biológica, IQUIFIB (UBA-CONICET), Facultad de Farmacia y Bioquí� mica, Universidad de Buenos Aires, 1113 Buenos Aires, Argentina release angiotensinogen (AGT) into the circulation, which contains at its N-terminal end the decapeptide Ang I that is released by the interaction of AGT with circulating renin [2]. The angiotensin converting enzyme (ACE) is a dipeptidyl carboxypeptidase that catalyzes the hydrolysis of Ang I into Ang II [3].…”

“…Ang A is an octapeptide derived from Ang II with an amino acid sequence that differs from Ang II only in the first amino acid: alanine instead of aspartic [6]. Like Ang II, Ang- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12), Ang III and Ang A cause vasoconstriction and smooth muscle cell proliferation by activation of Ang II type 1 receptor (AT1R) [7][8][9]. At the peripheral level, Ang III induces natriuresis and diuresis by acting on Ang II type 2 receptor (AT2R) [10].…”