Cycles of structural destabilization and repair underlie evolutionary trajectories — ASN Events
  1. Schedule
  2. Session 14: Catalytic Machines
  3. Cycles of structural destabilization and repair underlie evolutionary trajectories

Cycles of structural destabilization and repair underlie evolutionary trajectories (#34)

Colin Jackson 1 , Nobuhiko Tokuriki 2 , Kaltenbach Miriam 2 , Campbell Eleanor 1
  1. ANU, Australian National University, ACT, Australia
  2. Michael Smith Laboratories, University British Columbia, Vancouver, BC, Canada

The ability of enzymes to evolve new functions is central to life and gives organisms the ability to adapt to a changing environment. However, while this process is qualitatively appreciated, the molecular processes that allow an enzyme to change its function are poorly understood. Our limited understanding impacts our ability to engineer functional changes - we can often replicate the initial steps in an evolutionary trajectory, but there are very few examples of a full functional transition of an enzyme occurring in a laboratory. To address this, we have performed a 22 generation molecular evolution experiment, yielding an evolutionary trajectory involving a 109-fold reversal in catalytic specificity.1 We have solved the structures of six enzymes along this trajectory, allowing us to examine a molecular ‘fossil record’ and observe the structural changes that underlie the functional switch. Our results show that cycles of destabilization, involving the introduction of functionally important mutations, and repair, in which second and third shell mutations re-optimize the conformational landscape of the enzyme,2 form the structural basis of evolvability. Examination of a more recent functional transition in a naturally occurring enzyme from the sheep blowfly3 shows that this process is likely to occur in a general fashion in enzyme evolution.

1.    Tokuriki N, Jackson CJ, Afriat-Jurnou L, Wyganowski KT, Tang R, Tawfik DS. (2012) Diminishing returns and tradeoffs constrain the laboratory optimization of an enzyme. Nat Commun. 3:1257.

2.    Jackson CJ, Foo JL, Tokuriki N, Afriat L, Carr PD, Kim HK, Schenk G, Tawfik DS, Ollis DL. (2009) Conformational sampling, catalysis, and evolution of the bacterial phosphotriesterase. Proc Natl Acad Sci U S A. 206(51):21631-6.

3.    Jackson CJ, Liu JW, Carr PD, Younus F, Coppin C, Meirelles T, Lethier M, Pandey G, Ollis DL, Russell RJ, Weik M, Oakeshott JG. (2013) Structure and function of an insect α-carboxylesterase (αEsterase7) associated with insecticide resistance. Proc Natl Acad Sci U S A. 110(25):10177-82.