Behan D P, De Souza E B, Lowry P J, Potter E, Sawchenko P, Vale W W
Neurocrine Biosciences Inc., San Diego, California 92121, USA.
Front Neuroendocrinol. 1995 Oct;16(4):362-82. doi: 10.1006/frne.1995.1013.
A 37-kDa corticotropin releasing factor (CRF) binding protein (CRF-BP) was purified from human plasma by repeated affinity purification and subsequently sequenced and cloned. The human and rat CRF-BP cDNAs encode proteins of 322 amino acids with one putative signal sequence, one N-glycosylation site, and 10 conserved cysteines. Human CRF-BP binds human CRF with high affinity but has low affinity for the ovine peptide. In contrast, sheep CRF-BP binds human and ovine CRF with high affinity. The CRF-BP gene consists of seven exons and six introns and is located on chromosome 13 and loci 5q of the mouse and human genomes, respectively. CRF-BP inhibits the adrenocorticotrophic hormone (ACTH) releasing properties of CRF in vitro. CRF-BP dimerizes after binding CRF and clears the peptide from blood. This clearance mechanism protects the maternal pituitary gland from elevated plasma CRF levels found during the third trimester of human pregnancy. CRF-BP is expressed in the brains of all species so far tested but is uniquely expressed in human liver and placenta. In brain, CRF-BP is membrane associated and is predominantly expressed in the cerebral cortex and subcortical limbic structures. In some brain areas CRF-BP colocalizes with CRF and CRF receptors. The protein is also present in pituitary corticotropes, where it is under positive glucocorticoid control, and is likely to locally modulate CRF-induced ACTH secretion. The ligand requirements of the CRF receptor and the CRF-BP can be distinguished in that central human CRF fragments, such as CRF (6-33) and CRF (9-33), have high affinity for CRF-BP but low affinity for the CRF receptor. The binding protein's ability to inhibit CRF-induced ACTH secretion can be reversed by CRF (6-33) and CRF (9-33), suggesting that ligand inhibitors may have utility in elevating free CRF levels in disease states associated with decreased CRF. Thus, by controlling the amount of free CRF which activates CRF receptors, it is likely that the CRF-BP is an important modulator of CRF both in the CNS and in the periphery.
通过反复亲和纯化从人血浆中纯化出一种37 kDa的促肾上腺皮质激素释放因子（CRF）结合蛋白（CRF-BP），随后对其进行测序和克隆。人和大鼠的CRF-BP cDNA编码含一个假定信号序列、一个N-糖基化位点和10个保守半胱氨酸的322个氨基酸的蛋白质。人CRF-BP与人CRF具有高亲和力，但对绵羊肽的亲和力较低。相反，绵羊CRF-BP与人及绵羊CRF均具有高亲和力。CRF-BP基因由7个外显子和6个内含子组成，分别位于小鼠和人类基因组的13号染色体以及5q位点。CRF-BP在体外可抑制CRF的促肾上腺皮质激素（ACTH）释放特性。CRF-BP在与CRF结合后会二聚化，并从血液中清除该肽。这种清除机制可保护母体垂体免受人类妊娠晚期血浆CRF水平升高的影响。CRF-BP在迄今为止所检测的所有物种的大脑中均有表达，但在人类肝脏和胎盘中有独特表达。在大脑中，CRF-BP与膜相关，主要表达于大脑皮层和皮层下边缘结构。在某些脑区，CRF-BP与CRF及CRF受体共定位。该蛋白也存在于垂体促肾上腺皮质细胞中，在那里它受糖皮质激素正向调控，可能在局部调节CRF诱导的ACTH分泌。CRF受体和CRF-BP对配体的需求可通过以下方式区分：人中枢CRF片段，如CRF（6-33）和CRF（9-33），对CRF-BP具有高亲和力，但对CRF受体的亲和力较低。CRF（6-33）和CRF（9-33）可逆转结合蛋白抑制CRF诱导的ACTH分泌的能力，这表明配体抑制剂可能在与CRF降低相关的疾病状态下提高游离CRF水平方面具有效用。因此，通过控制激活CRF受体的游离CRF量，CRF-BP很可能是中枢神经系统和外周CRF的重要调节因子。
