Translocation boost protein-folding efficiency of double-barreled chaperonins

¹ Cambridge University Centre for Computational Chemistry
² Vrije Universiteit
³ FOM Institute for Atomic and Molecular Physics

^* To whom correspondence should be addressed. E-mail: ic247{at}cam.ac.uk.

Submitted on September 23, 2005
Revised on December 10, 2005
Accepted on 11 January 2006

	Abstract

Incorrect folding of proteins in living cells may lead to malfunctioning of the cell machinery. To prevent such cellular disasters from happening, all cells contain molecular chaperones that assist non-native proteins to fold into the correct native structure. One of the most studied chaperone complexes is the GroEL-GroES complex. The GroEL part has a "double-barrel" structure, which consists of two cylindrical chambers, joined at the bottom in a symmetrical fashion. The hydrophobic rim of one of the GroEL chambers captures non-native proteins. The GroES part acts as a lid that temporarily closes the filled chamber during the folding process. Several capture-folding-release cycles are required before the non-native protein reaches its native state. Here we report molecular simulations that suggest that translocation of the non-native protein through the equatorial plane of the complex boost the efficiency of the chaperonin action. If the target protein is correctly folded after translocation it is released. However, if it is still non-native, it is likely to remain trapped in the second chamber, which then closes to start a reverse translocation process. This shuttling back and forth continues until the protein is correctly folded. Our model provides a natural explanation for the prevalence of double-barreled chaperonins. Moreover, we argue that internal folding is both more efficient and safer than a scenario where partially refolded proteins escape from the complex before being recaptured.

Key Words: Chaperonin, GroEL-GroES, Lattice Heteropolymers, Protein Design, Protein Folding, Translocation