Glenn Millhauser, Department of Chemistry

	This sequence representation of PrPC locates the globular C-terminal domain, the glycosylphosphatidylinositol (GPI) membrane anchor and the octarepeat domain. Also shown is a flexible region implicated in multimerization that accompanies PrC->PrPSc conversion. Cu2+ binding within the octarepeats involves the specific residues HGGGW (underlined).
	Crystal structure of the Cu2+ binding site showing how glycine coordinates through deprotonated amide bonds. This unusual binding site may offer important clues into PrP's physiological function.

In modern biochemistry, structural determination is essential for understanding the function of biomolecules. Scientists in Glenn Millhauser's laboratory use peptide synthesis, nuclear magnetic resonance spectroscopy (NMR), and electron paramagnetic spin resonance spectroscopy (EPR) to examine the structure and analyze the function of proteins that have been implicated in several debilitating diseases. This includes the prion protein, which is responsible for mad cow disease and the related human affliction, Creutzfeldt-Jakob disease.

Prions: What Are They Good For?

The prion protein (PrP) is a globular, membrane-bound, glycoprotein found in all mammals and avian species. Nearly twenty years ago, it was found to be responsible for a class of fatal, dementia diseases, called transmissible spongiform encephalopathies (TSEs). Despite years of research on this remarkable protein, PrP's normative physiological function remained unclear.

Recent work, however, has demonstrated that the flexible N-terminal domain of PrP binds copper ions cooperatively and with high affinity. New physiological studies suggest that PrP plays a crucial role in copper homeostasis within the central nervous system. This is a remarkable development and connects beautifully with current interests in biological mechanisms of copper trafficking and hypotheses about the interplay between improper metal ion regulation and neurological disease.

Mature PrP is approximately 200 residues long and the majority of copper binding takes place in an unusual domain composed of repeating PHGGGWGQ sequences. Millhauser's lab has recently determined the structure of the PrP copper-binding site. They are currently investigating possible neurological functions associated with this site, including the possibility that PrP's normal function is to sense copper concentrations in the central nervous system or transport copper through endocytosis. They are also investigating how copper participates in the conversion of PrP to its pathogenic form.