Thursday, April 23, 2009

unboiling eggs

Helen Saibil's group at Birkbeck has a very interesting paper out in Molecular Cell this month:

Motor Mechanism for Protein Threading through Hsp104

Petra Wendler, James Shorter, David Snead, Celia Plisson, Daniel K. Clare, Susan Lindquist and Helen R. Saibil,

Molecular Cell Volume 34, Issue 1, 10 April 2009, Pages 81-92 PDF


Here's a press release I have helped to prepare:

How to unboil an egg

Scientists at Birkbeck College, London, working with colleagues in the US, have revealed how a cellular machine can “unboil an egg”.

The proteins that carry out a wide variety of essential tasks within our cells typically have to acquire a specific shape to be able to function properly. In the process known as protein folding, their long chain of amino acid building blocks is wound up and pleated into a complex pattern that is characteristic for each protein. This process can go off the rails, however, due to environmental stress or disease. Misfolding of proteins can cause them to clump together into aggregates, which is what happens when we boil an egg, or to into extended fibres, which are a hallmark of diseases such as Alzheimer’s and BSE. The formation of such aggregates or fibrils is normally irreversible.

Yeast cells, however, possess a remarkable protein known as heat shock protein 104 (HSP104), which is able to reverse aggregation, so it can, in principle, “unboil an egg.” This ability is of great medical interest as it may lead to ways of treating diseases like Alzheimer’s. While humans don’t have this protein, researchers hope that they will eventually be able to introduce something like it to fight disease.

The group of Helen Saibil at Birkbeck College, London, in collaboration with Susan Lindquist at the Whitehead Institute in Cambridge, Massachusetts, has now used cryo electron microscopy (cryo-EM) to obtain detailed images of the unboiling machine in various phases of its function, allowing researchers get a first view of how it manages to dissolve aggregates. Lindquist was one of the first to discover that Hsp104 has this unique disaggregation activity.

The machine consists of six identical, elongated protein molecules arranged in a barrel shape. Each of the molecules consists of three distinct parts (domains), so the barrel can also be thought of as a stack of three rings, each consisting of six identical domains.

Any misfolded proteins to be processed by the machine will enter through a fairly narrow ring formed by the first domain of each protein. Then the middle ring of the machine springs into action, using the cellular fuel ATP to move the amino acid chain onwards, and to pull it further in, which helps to disentangle it from the aggregates it was trapped in. The domains forming the last ring also have an ATP-fuelled activity, so both rings work together to pull the thread through the barrel. The cryo-EM images reveal that the domains of the protein undergo surprisingly large movements directly linked to its binding and consumption of ATP. Cycles of repeated binding, movement and release drag the protein chain through the barrel.

When this process happens in the yeast cell, a folding helper protein will be ready at the far side of the complex to help restore the disentangled protein chain to its proper form and function.

Lead investigator Helen Saibil said: “It is very important to understand this disentangling machine in yeast, as there are so many human diseases now linked to protein aggregates, and understanding yeast may eventually help to cure human patients.”

No comments:

Related Posts with Thumbnails