MBE Advance Access published online on November 7, 2006
Molecular Biology and Evolution, doi:10.1093/molbev/msl168
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Fundació irsiCaixa Universita,t Autònoma de Barcelona (UAB), Spain
* To whom correspondence should be addressed. Protein evolution has occurred by successive fixation of individual mutations. The probability of fixation depends on the fitness of the mutation, the arising variant can be deleterious, neutral, or beneficial. Despite its relevance only few studies have estimated the distribution of fitness effects caused by random single mutations on protein function. The HIV-1 protease was chosen as a model protein to quantify protein's tolerability to random single mutations. After determining the enzymatic activity of 107 single random mutants, we found that 86 % of single mutations were deleterious for the enzyme catalytic efficiency and 54 % lethal. Only 2 % of the mutations significantly increased the catalytic efficiency of the enzyme. These data demonstrates the vulnerability of HIV-1 protease to single random mutations. When a second random mutagenesis library was constructed from an HIV-1 protease carrying a highly deleterious single mutation (D30N), a higher proportion of mutations with neutral or beneficial effect was found, 26% and 9%, respectively. Importantly, antagonist epistasis was observed between deleterious mutations. In particular, the mutation N88D, lethal for the wild-type protease, restored the wild-type catalytic efficiency when combined with the highly deleterious mutation D30N. The low tolerability to single random substitutions shown here for the wild-type HIV-1 protease contrasts with its in vivo ability to generated an adaptive variation. Thus, the antagonist epistasis between deleterious or lethal mutations may be responsible for increasing the protein mutational robustness and evolvability.
Accepted November 2, 2006
Research Article
HIV-1 Protease Catalytic Efficiency Effects Caused by Random Single Amino Acid Substitutions
Mariona Parera 1, Guerau Fernàndez 1, Bonaventura Clotet 1, and Miguel Angel Martínez 1 *
Miguel Angel Martínez, E-mail: mmartinez{at}irsicaixa.es
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. Fernandez, B. Clotet, and M. A. Martinez Fitness Landscape of Human Immunodeficiency Virus Type 1 Protease Quasispecies J. Virol., March 1, 2007; 81(5): 2485 - 2496. [Abstract] [Full Text] [PDF]
|
|