RANDOM COIL CONFORMATION FOR EXTENDED POLYGLUTAMINE STRETCHES IN AQUEOUS SOLUBLE MONOMERIC PEPTIDES

Several neurodegenerative diseases have been found to be strongly asso ciated with proteins containing a polyglutamine stretch which is great ly expanded from approximately 20 glutamines in normal individuals to more than 40 in affected individuals. A conformational change in the e xpanded polyglutamine stretch has been suggested to form the molecular basis for disease onset. Model peptides containing polyglutamine tend to aggregate and become insoluble. We have synthesized readily water- soluble monomeric peptides by flanking polyglutamine stretches with se quences rich in alanine and lysine. Circular dichroism measurements sh ow that polyglutamine stretches of length 9 or 17 adopt a random coil configuration in aqueous solution. We think that in the disease-associ ated peptides for normal individuals the stretches of similar to 20 gl utamines are in a random coil conformation, whereas in affected indivi duals the polyglutamine stretch may be in some other conformation. Our method to design soluble monomeric peptides containing extended polyg lutamine stretches may be generally useful in studying other highly ag gregating peptides. (C) Munksgaard 1997.