Friday, January 14, 2011

Ribosome-assisted protein UN-folding

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"Stand still, do not move! I gave you life, I will also kill you!" said Taras, and, retreating a step backwards, he brought his gun up to his shoulder. Andrii was white as a sheet; his lips moved gently, and he uttered a name; but it was not the name of his native land, nor of his mother, nor his brother; it was the name of the beautiful Pole. Taras fired.

Ribosome makes proteins, we all know that. But producing a string of amino acids is just a half it. In order to be functional, nascent protein should fold correctly. And the ribosome takes care of that as well.

First, building blocks of the protein - alfa helices, for instance - are formed already in the ribosomal tunnel where they are protected from the hostile environment. When the protein emerges outside of the tunnel, it is greeted by the ribosome-associated chaperons, which help it to fold. Moreover, by cleverly fine-tuning translational rate, protein syntheses machinery allows protein domains to be produced one by one with pauses in between, ensuring that they fold correctly.

And here is a surprise. A fresh paper in JACS by O'Brian and colleagues suggest that the ribosome destabilizes unfinished proteins dangling out of the ribosome tunnel. Coarse-grain simulations allow dissecting the nature of this phenomenon.

Stability of the protein is reflected by the Gibbs free energy of folding (ΔG). Gibbs free energy in turn can be divided into and enthalpic (ΔH) and entropic components (TΔS), ΔG = ΔH - TΔS. When the protein is close to the ribosome, it pays for it in freedom (obviously, it can't move about freely any more), which means that the total number of available microstates is lower. And S is dependent on the total number of these microstates, thus it goes down, bringing down the Gibbs free energy. 

Moreover, it is not just thermodynamics, it is kinetics too: ribosome decreases folding rate, and unfolding rate increases. This is keeping with the basic definitions relating the equilibrium constant (K) with the rate ones (k+1,  k-1), ΔG = - RTln(K), K = k+1 / k-1.

So why is the ribosome so nasty to its progeny? Well, I guess the answer is - it just can't help it. The effects described above are simple consequences of the fact that nascent protein has to be attached to the ribosome during translation, and this results in loss in available microstates and so on (see above). And translational machinery is trying hard to be kinder to nascent proteins, cleverly designing the ribosomal tunnel, employing chaperones and waiting for the domains to fold before moving to the next one.

But is the ribosome doing anything good to the folding protein? And yes, it does. It stirs the folding pathway towards more native-like intermediates, guiding the direction of folding so that it starts from the N-terminus - the part that gets translated first. And again, this beneficial effect is done again by restricting proteins' freedom - freedom to sample configurations diverging from the productive folding path. 

Isn't it a great example of excellent parenting?  


O'Brien EP, Christodoulou J, Vendruscolo M, & Dobson CM (2011). New Scenarios of Protein Folding Can Occur on the Ribosome. Journal of the American Chemical Society PMID: 21204555

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