TIFR
Department of Chemical Sciences
School of Natural Sciences

March 5, 2018 at 4.00 pm in AG-69

Title :

Xeno-nuclei enable protein-specific modulation of order-disorder transition

Abstract :

The ability to modulate the order to disorder or vice versa transition of a specific protein in a milieu of many proteins can be an important tool for chemical biology and pharmacology. Kinetics and thermodynamics of protein folding are routinely modulated by changing solvent conditions, but such changes are not very protein specific. Specific ligands with the ability to alter the stability of a 

protein are rarely available. Here, we propose a general approach for designing such ligands by mimicking the folding nucleus of a protein. The key idea is to choose a part of the protein itself, which is suspected/known to be the nucleation site for the folding pathway, and then to put it in a pre-formed shape to modulate the folding/unfolding. This xeno-nucleus can in principle, be used to selectively modulate the folding of a particular protein from a mixture of different proteins. 

We show that the ⓵ - ⓶ part (residues 1 to 17) of ubiquitin [1], which is known to fold into a β-hairpin shape and to nucleate the folding of the rest of the protein, can make folding faster when it is introduced as a separate peptide at excess concentrations. No such acceleration is observed when the xeno-nucleus is unfolded to start with. Interestingly, the protein also becomes less stable, as the unfolding rate becomes even faster. We show that this effect is protein-specific, as another protein with no such β-hairpin (e.g. bovine serum albumin) remains unaffected by the peptide. Our results suggest that the folding of almost any protein that possesses a well-defined folding nucleus can be modulated, if a nucleus-mimicking molecule with a stabilized structure can be constructed. 

References: 

1. Atomic-level description of ubiquitin folding. PNAS, 2013, 110 (15), 5915–5920.