Extensive site-directed mutagenesis reveals interconnected functional units in the alkaline phosphatase active site

Sunden, Fanny; Peck, Ariana; Salzman, Julia; Ressl, Susanne; Herschlag, Daniel

doi:10.7554/eLife.06181

Title: Extensive site-directed mutagenesis reveals interconnected functional units in the alkaline phosphatase active site

Journal Article · Wed Apr 22 00:00:00 EDT 2015 · eLife

DOI:https://doi.org/10.7554/eLife.06181· OSTI ID:1182427

Sunden, Fanny ^[1]; Peck, Ariana ^[1]; Salzman, Julia ^[1]; Ressl, Susanne ^[2]; Herschlag, Daniel ^[1]

Department of Biochemistry, Beckman Center, Stanford University, Stanford, United States
Molecular and Cellular Biochemistry Department, Indiana University Bloomington, Bloomington, United States

Enzymes enable life by accelerating reaction rates to biological timescales. Conventional studies have focused on identifying the residues that have a direct involvement in an enzymatic reaction, but these so-called ‘catalytic residues’ are embedded in extensive interaction networks. Although fundamental to our understanding of enzyme function, evolution, and engineering, the properties of these networks have yet to be quantitatively and systematically explored. We dissected an interaction network of five residues in the active site of Escherichia coli alkaline phosphatase. Analysis of the complex catalytic interdependence of specific residues identified three energetically independent but structurally interconnected functional units with distinct modes of cooperativity. From an evolutionary perspective, this network is orders of magnitude more probable to arise than a fully cooperative network. From a functional perspective, new catalytic insights emerge. Further, such comprehensive energetic characterization will be necessary to benchmark the algorithms required to rationally engineer highly efficient enzymes.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); National Center for Research Resources (NCRR); National Institute of General Medical Sciences (NIGMS); National Science Foundation (NSF)

Grant/Contract Number:: Office of Biological and Environmental Research; AC02-76SF00515; GM64798; GM049243

OSTI ID:: 1182427

Alternate ID(s):: OSTI ID: 1198402; OSTI ID: 1628834

Journal Information:: eLife, Journal Name: eLife Vol. 4; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 48 works

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