Asymmetric processing of a substrate protein in sequential allosteric cycles of AAA+ nanomachines

Kravats, Andrea N.; Tonddast-Navaei, Sam; Bucher, Ryan J.; Stan, George
September 2013
Journal of Chemical Physics;Sep2013, Vol. 139 Issue 12, p121921
Academic Journal
Essential protein quality control includes mechanisms of substrate protein (SP) unfolding and translocation performed by powerful ring-shaped AAA+ (ATPases associated with various cellular activities) nanomachines. These SP remodeling actions are effected by mechanical forces imparted by AAA+ loops that protrude into the central channel. Sequential intra-ring allosteric motions, which underlie repetitive SP-loop interactions, have been proposed to comprise clockwise (CW), counterclockwise (CCW), or random (R) conformational transitions of individual AAA+ subunits. To probe the effect of these allosteric mechanisms on unfoldase and translocase functions, we perform Langevin dynamics simulations of a coarse-grained model of an all-alpha SP processed by the single-ring ClpY ATPase or by the double-ring p97 ATPase. We find that, in all three allosteric mechanisms, the SP undergoes conformational transitions along a common set of pathways, which reveals that the active work provided by the ClpY machine involves single loop-SP interactions. Nevertheless, the rates and yields of SP unfolding and translocation are controlled by mechanism-dependent loop-SP binding events, as illustrated by faster timescales of SP processing in CW allostery compared with CCW and R allostery. The distinct efficacy of allosteric mechanisms is due to the asymmetric collaboration of adjacent subunits, which involves CW-biased structural motions of AAA+ loops and results in CW-compatible torque applied onto the SP. Additional simulations of mutant ClpY rings, which render a subset of subunits catalytically-defective or reduce their SP binding affinity, reveal that subunit-based conformational transitions play the major role in SP remodeling. Based on these results we predict that the minimally functional AAA+ ring includes three active subunits, only two of which are adjacent.


Related Articles

  • Chaperone-Assisted Protein Folding in the Cell Cytoplasm. Houry, Walid A. // Current Protein & Peptide Science;Sep2001, Vol. 2 Issue 3, p227 

    Folding of polypeptides in the cell typically requires the assistance of a set of proteins termed molecular chaperones. Chaperones are an essential group of proteins necessary for cell viability under both normal and stress conditions. There are several chaperone systems which carry out a...

  • Allosteric Modulators.  // Encyclopedic Reference of Molecular Pharmacology;2004, p26 

    The article presents an encyclopedia entry for allosteric modulators. They bind to their own site on the receptor and produce an effect on agonism through a protein conformational change. They can affect the affinity of the receptor for the agonist. The effect reaches a maximal asymptote...

  • Proteomic analysis of the response to high-salinity stress in Physcomitrella patens. Xiaoqin Wang; Pingfang Yang; Qian Gao; Xianglin Liu; Tingyun Kuang; Shihua Shen; Yikun He // Planta;May2008, Vol. 228 Issue 1, p167 

    Physcomitrella patens is well known because of its importance in the study of plant systematics and evolution. The tolerance of P. patens for high-salinity environments also makes it an ideal candidate for studying the molecular mechanisms by which plants respond to salinity stresses. We...

  • Quality control of protein folding in extracellular space. Yerbury, Justin J.; Stewart, Elise M.; Wyatt, Amy R.; Wilson, Mark R. // EMBO Reports;Dec2005, Vol. 6 Issue 12, p1131 

    The pathologies of many serious human diseases are thought to develop from the effects of intra- or extracellular aggregates of non-native proteins. Inside cells, chaperone and protease systems regulate protein folding; however, little is known about any corresponding mechanisms that operate...

  • Thinking outside the box: new insights into the mechanism of GroEL-mediated protein folding. Wang, Jue D.; Weissman, Jonathan S. // Nature Structural Biology;Jul99, Vol. 6 Issue 7, p597 

    GroEL is thought to assist protein folding in part by providing a passive 'box' in which folding can occur without danger of aggregation. Two new papers now suggest that GroEL can also play a more active role by promoting rearrangement and even unfolding of kinetic folding intermediates.

  • The complete folding pathway of a protein from nanoseconds to microseconds. Mayor, Ugo; Guydosh, Nicholas R.; Johnson, Christopher M.; Grossmann, J. Günter; Sato, Satoshi; Jas, Gouri S.; Freund, Stefan M. V.; Alonso, Darwin O. V.; Daggett, Valerie; Fersht, Alan R. // Nature;2/20/2003, Vol. 421 Issue 6925, p863 

    Combining experimental and simulation data to describe all of the structures and the pathways involved in folding a protein is problematical. Transition states can be mapped experimentally by φ values, but the denatured state is very difficult to analyse under conditions that favour folding....

  • Folding consensus? Baldwin, Robert L. // Nature Structural Biology;Feb2001, Vol. 8 Issue 2, p92 

    Deals with studies that address contradictions about the use of the hierarchic mechanism for the folding process in both two-state and three-state folding reactions. Discussion on the β-lactoglobulin foldingl Im7 folding; Folding simulations.

  • Connecting statistical and optimized potentials in protein folding via a generalized foldability criterion. Saven, Jeffery G. // Journal of Chemical Physics;4/8/2003, Vol. 118 Issue 14, p6133 

    Developing a predictive understanding of protein folding requires quantitative measures of sequence-structure compatibility. A folding criterion is presented whose optimization over a training set of structures yields the commonly used statistical and optimized potentials as two limiting cases,...

  • Investigation of the folding profiles of evolutionarily selected model proteins. Nelson, Erik; Grishin, Nick // Journal of Chemical Physics;2/15/2003, Vol. 118 Issue 7, p3342 

    Minimalist models of proteins, in which amino acid chains are represented by a necklace of beads that reconfigure the native fold on the sites of a cubic lattice, have been an important tool to infer early events in folding and to typify the energy landscapes of small globular proteins. In this...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics