CORTICOTROPIN-RELEASING FACTOR (CRF) BINDING-PROTEIN - A NOVEL REGULATOR OF CRF AND RELATED PEPTIDES

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 enco de proteins of 322 amino acids with one putative signal sequence, one N-glycosylation site, and 10 conserved cysteines. Human CRF-BP binds h uman CRF with high affinity but has low affinity for the ovine peptide . In contrast, sheep CRF-BP binds human and ovine CRF with high affini ty. The CRF-BP gene consists of seven exons and six introns and is loc ated on chromosome 13 and loci 5q of the mouse and human genomes, resp ectively. CRF-BP inhibits the adrenocorticotrophic hormone (ACTH) rele asing properties of CRF in vitro. CRF-BP dimerizes after binding CRF a nd clears the peptide from blood. This clearance mechanism protects th e maternal pituitary gland from elevated plasma CRF levels found durin g the third trimester of human pregnancy. CRF-BP is expressed in the b rains of all species so far tested but is uniquely expressed in human liver and placenta. In brain, CRF-BP is membrane associated and is pre dominantly expressed in the cerebral cortex and subcortical limbic str uctures. In some brain areas CRF-BP colocalizes with CRF and CRF recep tors. The protein is also present in pituitary corticotropes, where it is under positive glucocorticoid control, and is likely to locally mo dulate 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 ab ility 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 decrea sed CRF. Thus, by controlling the amount of free CRF which activates C RF receptors, it is likely that the CRF-BP is an important modulator o f CRF both in the CNS and in the periphery. (C) 1995 Academic Press, I nc.