The pyruvate kinase model system, a cautionary tale for the use of osmolyte perturbations to support conformational equilibria in allostery.

Protein Science : a Publication of the Protein Society
Aron W FentonTodd Holyoak

Abstract

In the study of rabbit muscle pyruvate kinase (M1-PYK), proline has previously been used as an osmolyte in an attempt to determine a role for preexisting conformational equilibria in allosteric regulation. In this context, osmolytes are small molecules assumed to have no direct interaction with the protein. In contrast to proline's proposed role as an osmolyte, the structure of M1PYK-Mn-pyruvate-proline complex reported herein demonstrates that proline binds specifically to the allosteric site of M1-PYK. Therefore, this amino acid is an allosteric effector rather than a benign osmolyte. Other compounds often used as osmolytes (polyethyleneglycol and glycerol) are also present in the structure, suggesting an interaction with the protein that would, in turn, prevent the usefulness of these compounds in the study of this and most likely other proteins. These findings highlight the need to verify that compounds used as osmolytes to perturb preexisting conformational equilibrium do not directly interact with the protein, a consideration not commonly addressed in the past.

Citations

Jun 13, 2015·Royal Society Open Science·Hugh P MorganMalcolm D Walkinshaw
May 12, 2016·Biophysical Journal·Gerald M Carlson, Aron W Fenton
Apr 4, 2017·Human Mutation·Qifang XuRoland L Dunbrack
May 12, 2018·The Biochemical Journal·Meng YuanMalcolm D Walkinshaw
Sep 4, 2013·Acta Crystallographica. Section D, Biological Crystallography·Wenhe ZhongMalcolm D Walkinshaw
Jun 26, 2020·The Journal of Physical Chemistry. B·Deepika NambiarElizabeth E Howell

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