William J. Dower

Functional Mimicry of a Protein Hormone by a Peptide Agonist: The EPO Receptor Complex at 2.8 Å

The functional mimicry of a protein by an unrelated small molecule has been a formidable challenge. Now, however, the biological activity of a 166-residue hematopoietic growth hormone, erythropoietin (EPO), with its class 1 cytokine receptor has been mimicked by a 20-residue cyclic peptide unrelated in sequence to the natural ligand. The crystal structure at 2.8 Å resolution of a complex of this agonist peptide with the extracellular domain of EPO receptor reveals that a peptide dimer induces an almost perfect twofold dimerization of the receptor. The dimer assembly differs from that of the human growth hormone (hGH) receptor complex and suggests that more than one mode of dimerization may be able to induce signal transduction and cell proliferation. The EPO receptor binding site, defined by peptide interaction, corresponds to the smaller functional epitope identified for hGH receptor. Similarly, the EPO mimetic peptide ligand can be considered as a minimal hormone, and suggests the design of nonpeptidic small molecule mimetics for EPO and other cytokines may indeed be achievable.

Aplysia californica: Analysis of Nuclear DNA in Individual Nuclei of Giant Neurons

The nuclei of the giant neurons of the marine mollusk Aplysia californica can contain more than 0.2 microgram of DNA. This is more than 200,000 times as much DNA as the haploid amount found in Aplysia sperm. On the basis of nuclear DNA content, the giant neurons R-2, P-1, and L-6 of adult animals can each be divided into at least two populations. The mean DNA content of these two populations (0.067 and 0.131 microgram of DNA) are approximately related by a factor of 2. This suggests that much and perhaps all of the genome replicates repeatedly (up to 16 times) during the growth and development of these neurons and that each replication is synchronous. The enormous amount of DNA in these cells opens up the possibility of characterizing the DNA and other constituents of chromatin from individual but phenotypically different neurons.