Evolvability as a function of purifying selection in TEM-1 β-lactamase.


Abstract

Evolvability—the capacity to generate beneficial heritable variation—is a central property of biological systems. However, its origins and modulation by environmental factors have not been examined systematically. Here, we analyze the fitness effects of all single mutations in TEM-1 β-lactamase (4,997 variants) under selection for the wild-type function (ampicillin resistance) and for a new function (cefotaxime resistance). Tolerance to mutation in this enzyme is bimodal and dependent on the strength of purifying selection in vivo, a result that derives from a steep non-linear ampicillin-dependent relationship between biochemical activity and fitness. Interestingly, cefotaxime resistance emerges from mutations that are neutral at low levels of ampicillin but deleterious at high levels; thus the capacity to evolve new function also depends on the strength of selection. The key property controlling evolvability is an excess of enzymatic activity relative to the strength of selection, suggesting that fluctuating environments might select for high-activity enzymes.

Submission Details

ID: 2EATsCpD3

Submitter: Shu-Ching Ou

Submission Date: July 24, 2018, 2:40 p.m.

Version: 1

Publication Details
Stiffler MA;Hekstra DR;Ranganathan R,Cell (2015) Evolvability as a function of purifying selection in TEM-1 β-lactamase. PMID:25723163
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
1AXB 1997-10-14T00:00:00+0000 2.0 TEM-1 BETA-LACTAMASE FROM ESCHERICHIA COLI INHIBITED WITH AN ACYLATION TRANSITION STATE ANALOG
1BT5 1998-09-02T00:00:00+0000 1.8 CRYSTAL STRUCTURE OF THE IMIPENEM INHIBITED TEM-1 BETA-LACTAMASE FROM ESCHERICHIA COLI
1BTL 1993-11-01T00:00:00+0000 1.8 CRYSTAL STRUCTURE OF ESCHERICHIA COLI TEM1 BETA-LACTAMASE AT 1.8 ANGSTROMS RESOLUTION
1CK3 1999-04-27T00:00:00+0000 2.28 N276D MUTANT OF ESCHERICHIA COLI TEM-1 BETA-LACTAMASE
1ERM 2000-04-06T00:00:00+0000 1.7 X-RAY CRYSTAL STRUCTURE OF TEM-1 BETA LACTAMASE IN COMPLEX WITH A DESIGNED BORONIC ACID INHIBITOR (1R)-1-ACETAMIDO-2-(3-CARBOXYPHENYL)ETHANE BORONIC ACID
1ERO 2000-04-06T00:00:00+0000 2.1 X-RAY CRYSTAL STRUCTURE OF TEM-1 BETA LACTAMASE IN COMPLEX WITH A DESIGNED BORONIC ACID INHIBITOR (1R)-2-PHENYLACETAMIDO-2-(3-CARBOXYPHENYL)ETHYL BORONIC ACID
1ERQ 2000-04-06T00:00:00+0000 1.9 X-RAY CRYSTAL STRUCTURE OF TEM-1 BETA LACTAMASE IN COMPLEX WITH A DESIGNED BORONIC ACID INHIBITOR (1R)-1-ACETAMIDO-2-(3-CARBOXY-2-HYDROXYPHENYL)ETHYL BORONIC ACID
1ESU 2000-04-11T00:00:00+0000 2.0 S235A MUTANT OF TEM1 BETA-LACTAMASE
1FQG 2000-09-05T00:00:00+0000 1.7 MOLECULAR STRUCTURE OF THE ACYL-ENZYME INTERMEDIATE IN TEM-1 BETA-LACTAMASE
1JTD 2001-08-20T00:00:00+0000 2.3 Crystal structure of beta-lactamase inhibitor protein-II in complex with TEM-1 beta-lactamase

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
99.7 Beta-lactamase TEM Q48406 BLAT_KLEOX
100.0 Beta-lactamase TEM P62594 BLAT_SALTI
100.0 Beta-lactamase TEM P62593 BLAT_ECOLX