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Optimizing ring assembly reveals the strength of weak interactions

  1. Walter Fontanab,2
  1. Edited by José N. Onuchic, University of California at San Diego, La Jolla, CA, and approved December 27, 2011 (received for review August 13, 2011)

Abstract

Most cellular processes rely on large multiprotein complexes that must assemble into a well-defined quaternary structure in order to function. A number of prominent examples, including the 20S core particle of the proteasome and the AAA+ family of ATPases, contain ring-like structures. Developing an understanding of the complex assembly pathways employed by ring-like structures requires a characterization of the problems these pathways have had to overcome as they evolved. In this work, we use computational models to uncover one such problem: a deadlocked plateau in the assembly dynamics. When the molecular interactions between subunits are too strong, this plateau leads to significant delays in assembly and a reduction in steady-state yield. Conversely, if the interactions are too weak, assembly delays are caused by the instability of crucial intermediates. Intermediate affinities thus maximize the efficiency of assembly for homomeric ring-like structures. In the case of heteromeric rings, we find that rings including at least one weak interaction can assemble efficiently and robustly. Estimation of affinities from solved structures of ring-like complexes indicates that heteromeric rings tend to contain a weak interaction, confirming our prediction. In addition to providing an evolutionary rationale for structural features of rings, our work forms the basis for understanding the complex assembly pathways of stacked rings like the proteasome and suggests principles that would aid in the design of synthetic ring-like structures that self-assemble efficiently.

Footnotes

  • Author contributions: E.J.D., J.A.B., and W.F. designed research; E.J.D. and J.A.B. performed research; E.J.D., J.A.B., and W.F. analyzed data; and E.J.D., J.A.B., and W.F. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1113095109/-/DCSupplemental.

     

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