Are Allosteric Mechanisms Conserved Among Homologues?
Aron W. Fenton, Zoe A. Hoffpauir, Tyler A. Martin, Robert A. Harris, Audrey L. Lamb · Journal of Molecular Biology · 2025
Conservation of allosteric mechanisms among homologues is often assumed but seldom tested. This assumption underpins key concepts like coevolution of residues involved in allosteric mechanisms and the comparison of structures of two different homologues to gain insights into allosteric mechanisms. As an initial assessment of whether allosteric mechanisms are conserved among homologues, this work reviews what is known about the allosteric mechanisms of liver pyruvate kinase (LPYK) vs. skeletal muscle pyruvate kinase (M 1 PYK), framed within a two-ligand allosteric energy cycle description of allosteric regulation. Selective observations from other PYK homologues are included when relevant. The primary focus of this review is on functional data, while expressing caution regarding the interpretation of allosteric mechanisms based solely on available X-ray crystallographic structures. Additionally, this review considers types of data that are currently lacking for these two PYK homologues, highlighting potential techniques that could be valuable for evaluating the conservation of allosteric mechanisms among homologues. In particular, a hybrid tetramer technique that has been used to study bacterial phosphofructokinases 1 is summarized. Interestingly, despite a high degree of similarity (66.5% sequence identity) between the LPYK and rM 1 PYK proteins, the available functional comparisons do not provide strong evidence for conserved allosteric mechanisms. Lastly, we consider whether insights into native allosteric mechanisms are relevant to allosteric mechanisms associated with allosteric drug designs.