Aua

Cys (Tyr) (Phe)Gin Asn Cys Pro(Arg)Gly (NH2) Cys Tyr lie Gin Asn Cys Pro(Ceu)Gly <NHZ)

Recent gene duplication and substitution

UAU AGA

UUU Phenypressin Lysine vasopressin AAA

Cys (Phe) Phe Gin Asn Cys Pro Arg Gly (NH2) Cys Tyr Phe Gin Asn Cys Pro (LysJGly (NH2)

FIGURE 4-4 Evolution of posterior pituitary peptides of mammals. Mammals simultaneously produce two posterior pituitary hormones by gene duplication. Point mutations account for individual amino acid substitutions. Possible changes in nucleotide sequences accounting for point mutations are shown and substituted amino acids are circled. Reproduced from Lincoln, D. W., and Short, R. V., eds. (1984). "Reproduction in Mammals; Book III: Hormonal Control of Reproduction," 2nd ed. Cambridge Univ. Press, London and New York.

or OT (Figures 4-5 and 4-6) and the NP protein with which it complexes. NP I is associated with OT and NP II is associated with VP. The preprotein (Figure 47) is of about 20,000 molecular weight and is cleaved by proteases to an NP of about 9500-10,000 molecular weight (Figure 4-5). After removal of the signal peptide, the prohormone is cleaved at a dibasic signal (Gly-Lys-Arg), liberating OT extended by Gly-X-X, where X is a basic amino acid. These enzymes are subtilisin-like serine proteases. Afterward, the carboxy-terminal amino acids are removed by carboxypeptidase E.

The two NPs are very similar in structure, and either OT or VP can form a complex with either NP in vitro. In some cases, it has been reported that NPs contain lipids bonded noncovalently, such as cholesterol, phosphatidylcholine, phosphatidylethanolamine, phospha-tidylserine, and sphingomyelin. The significance of lipids in these proteins is not clear.

The half-life of VP or OT is increased dramatically from about 3 to about 10-20 min when it is complexed with NP in blood. The hormone-NP complex probably stabilizes the hormone within the neurosecretory granules, but following release from the secretory granule, it is unlikely that the complex survives in the bloodstream.

The first three amino acids of either hormone are active in binding to the NP molecule, as shown for OT in Figure 4-8. Binding of the hormone with the NP probably involves a conformational change in the latter. Cysteine 1 of the hormone incorporates its free amino group in an electrostatic linkage to a charged carboxyl group of the NP-binding site (Figure 4-8). This carboxyl group could be on a glutamate residue. Amino acids 2 (Tyr) and 3 (Phe) of VP (lie in OT) participate in hydrophobic interactions at the NP-binding site. The peptide bond between amino acid residues 2 and 3 appears to hydrogen bond to NP (Figure 4-8).

The amino acid sequences of NP I and NP II indicate extensive homology between the two. It has been shown that posterior pituitary hormones can be methylated (Arg or Lys residues are most likely), and it is surmised that the modified hormones will have altered biological activities. Apparently, NP serves only a stabilizing role insofar as the activities of the posterior pituitary hormones are concerned. Although NP is released in free form in the blood, a distinct activity of uncomplexed NP has not been found. In spite of this, in pathological states where vasopressin synthesis is impaired, such as in the Brattleboro rat and in diabetes

Glycoprotein

Vasopressin )-Neurophysin-h_|

Glycoprotein

Vasopressin )-Neurophysin-h_|

Capping Site Poly A Site

EXON A EXON B EXON C

FIGURE 4-5 Proposed structure of the VP gene, its translation product, and the matured peptides. The gene codes for arginine-VP, NP, and glycoprotein and contains two introns. The gene product, provasopressin, is indicated in the middle. Negative numbers indicate the amino acid sequence of the signal sequence, while the positive numbers indicate the prohormone sequence. The attached open circle on the matured glycoprotein product at the top right represents carbohydrate. VP and OT are expressed as polyproteins. Reproduced from Richter, D. (1983). Trends Biochem. Sci. 8, 278-281.

Capping Site Poly A Site

EXON A EXON B EXON C

FIGURE 4-5 Proposed structure of the VP gene, its translation product, and the matured peptides. The gene codes for arginine-VP, NP, and glycoprotein and contains two introns. The gene product, provasopressin, is indicated in the middle. Negative numbers indicate the amino acid sequence of the signal sequence, while the positive numbers indicate the prohormone sequence. The attached open circle on the matured glycoprotein product at the top right represents carbohydrate. VP and OT are expressed as polyproteins. Reproduced from Richter, D. (1983). Trends Biochem. Sci. 8, 278-281.

insipidus in humans, the only gene defects encountered are those in the gene sequence encoding VP-associated neurophysin.

The crystal structure of neurophysin II has been determined, and the dimer with two molecules of vasopressin hormone analog is shown in Figure 4-9. The neurophysin dimer is also indicated in Figure 4-7.

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