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Conformational Heterogeneity Within the LID Domain Mediates Substrate Binding to Escherichia coli Adenylate Kinase: Function Follows Fluctuations

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Dynamics in Enzyme Catalysis

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 337))

Abstract

Proteins exist as dynamic ensembles of molecules, implying that protein amino acid sequences evolved to code for both the ground state structure as well as the entire energy landscape of excited states. Accumulating theoretical and experimental evidence suggests that enzymes use such conformational fluctuations to facilitate allosteric processes important for substrate binding and possibly catalysis. This phenomenon can be clearly demonstrated in Escherichia coli adenylate kinase, where experimentally observed local unfolding of the LID subdomain, as opposed to a more commonly postulated rigid-body opening motion, is related to substrate binding. Because “entropy promoting” glycine mutations designed to increase specifically the local unfolding of the LID domain also affect substrate binding, changes in the excited energy landscape effectively tune the function of this enzyme without changing the ground state structure or the catalytic site. Thus, additional thermodynamic information, above and beyond the single folded structure of an enzyme–substrate complex, is likely required for a full and quantitative understanding of how enzymes work.

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Abbreviations

AK:

Adenylate kinase

AK(e):

E. coli adenylate kinase

Ala:

Alanine

AMP:

Adenosine monophosphate

AMPbd:

AMP binding domain of adenylate kinase

Ap5A:

P1,P5-di(adenosine-5′) pentaphosphate

ATP:

Adenosine triphosphate

BC:

Binding competent

BI:

Binding incompetent

CD:

Circular dichroism spectroscopy

CORE:

Core domain of adenylate kinase

CPMG:

Carr-Purcell-Meiboom-Gill

Gly:

Glycine

HSQC:

Heteronuclear single quantum coherence

Ile:

Isoleucine

ITC:

Isothermal titration calorimetry

K:

Equilibrium constant

LID:

LID domain of adenylate kinase

NMR:

Nuclear magnetic resonance spectroscopy

U:

Unfolded

Val:

Valine

ΔG :

Gibbs free energy

ΔS :

Entropy change

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Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555-1068, USA

    Travis P. Schrank

  2. Department of Biology, The Johns Hopkins University, Mudd Hall Room 117, 3400 N. Charles Street, Baltimore, MD, 21218, USA

    James O. Wrabl & Vincent J. Hilser

  3. T.C. Jenkins Department of Biophysics, The Johns Hopkins University, Mudd Hall Room 117A, 3400 N. Charles Street, Baltimore, MD, 21218, USA

    Vincent J. Hilser

Authors
  1. Travis P. Schrank
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  2. James O. Wrabl
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  3. Vincent J. Hilser
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Corresponding author

Correspondence to Vincent J. Hilser .

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Editors and Affiliations

  1. Department of Chemistry Department of Molecular and Cell Biology, University of California The california institute for Quantitativ, Berkeley, CA, USA

    Judith Klinman

  2. Department of Chemistry, University of Illinois at Urbana-Champai, Urbana, Illinois, USA

    Sharon Hammes- Schiffer

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Schrank, T.P., Wrabl, J.O., Hilser, V.J. (2013). Conformational Heterogeneity Within the LID Domain Mediates Substrate Binding to Escherichia coli Adenylate Kinase: Function Follows Fluctuations. In: Klinman, J., Hammes- Schiffer, S. (eds) Dynamics in Enzyme Catalysis. Topics in Current Chemistry, vol 337. Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2012_410

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