Lorne Protein report: the secrets of VII tripeptide

In Douglas Adams' A Hitchhiker's Guide to the Galaxy, humans learned that the answer to the question of "life, the universe and everything" is 42.

The late author would no doubt have been amused to learn that 7 and 6, the factors of 42, provide an insight into the mysteries of death, from lethal brain disorders like Alzheimer's and Parkinson's disease.

As Prof Luis Serrano, a board member of EMBLEM (the technology transfer company for the European Molecular Biology Laboratory) explained to the Lorne Conference on Protein Structure and Function: Six is the minimum number of peptides required for a protein to self-polymerise to form amyloid fibrils, the threat-like structures that are the base materials of the toxic deposits, or plaques, that accumulate in the brains of people with Alzheimer's and Parkinson's.

Taking liberties, the Roman numeral for 7 is VII -- which, in biochemistry, is code for the amino-acid sequence valine-isoleucine-isoleucine, which Serrano's team has found to be uniquely amyloidogenic.

There's something about the VII tripeptide that causes it to form amyloid fibrils, irrespective of which of the 20 amino acids fleshes out the catalytic hexapeptide.

Serrano said a computer analysis of the 35,000-odd genes in the human genome has revealed that at least 70 per cent of their protein-coding sequences contain at least one random hexapeptide capable of polymerising to form amyloid fibres.

"It's frightening, because the chances that you will have these sequences in your body are very high," Serrano said.

He said it raised a question: Why, if there are so many proteins potentially capable of giving rise to amyloid fibres, are there so few amyloid-induced diseases?

Although the polymerisation process typically involves the entire protein, the hexapeptide sequence always forms the core of the amyloid fibre, and the core sequence can lie at any site within the protein.

Serrano said this finding suggested the protein must be partially or fully unfolded to form amyloid fibrils. The proteins line up in anti-parallel formation, forming beta sheets, and the growing beta sheets form the fibrils.

The EMBL research team has shown that short peptides taken from large, amyloidogenic proteins can transform non-amyloidogenic proteins into forms that form amyloid fibrils. The researchers are using model systems to explore the processes underlying fibril formation.

Using a computer program, they have introduced randomly generated hexapeptides into a non-amyloidogenic protein, alpha spectrin SF3, to determine why some hexapeptides, and not others, have a strong tendency to form amyloid fibres.

They have identified 10 highly amyloidogenic hexapeptides -- the most potent of them, embodying the valine-isoleucine-isoleucine, formed fibrils in less than a day.

Within any hexapeptide, positions 2, 4 and 5 appear to be most critical -- positions 1, 3 and 6 can tolerate a wide range of amino acids, if positions 2, 4, and 5 are occupied by a select group of 'A-team' residues.

While VII is the nastiest of them all, hexapeptides containing a VIV (valine-isoleucine-valine) core are completely non-amyloidogenic -- the packing between the beta sheets creates a cavity that is filled by water, disrupting the chemical binds that cross-link and stabilise the layered beta sheets.

Serrano said his team believes the rarity of amyloid-induced diseases in humans reflects strong selection against the most highly amyloidogenic sequences. They are likely to be more common in the proteins of short-lived species like mice, because they do not live long enough to accumulate a lethal load of amyloid in their brains.

The EMBL team has identified a mummer of compounds that break up the amyloid fibrils -- they have used the peptide sequences to screen for compounds that will break up whole-protein amyloid fibrils.

Australian Biotechnology News journalists will be on the ground at the Lorne Protein, Cancer and Genome conferences, presenting regular updates.