Are Allosteric Mechanisms Conserved Among Homologues?

Area of Science:

• Biochemistry
• Molecular Biology
• Enzyme Regulation

Background:

• Allosteric mechanisms are crucial for enzyme regulation but their conservation across homologous proteins is often assumed without rigorous testing.
• This assumption influences interpretations of residue coevolution and structural comparisons for understanding allosteric regulation.

Purpose of the Study:

• To assess the conservation of allosteric mechanisms between liver pyruvate kinase (LPYK) and skeletal muscle pyruvate kinase (M1PYK).
• To critically evaluate the reliance on structural data versus functional data for inferring allosteric mechanisms.

Main Methods:

• Review of existing functional and structural data for LPYK and M1PYK.
• Analysis within a two-ligand allosteric energy cycle framework.
• Consideration of data gaps and potential experimental techniques, including a hybrid tetramer approach.

Main Results:

• Despite 66.5% sequence identity between LPYK and rat M1PYK (rM1PYK), available functional data does not strongly support conserved allosteric mechanisms.
• Interpretation of allosteric mechanisms solely from X-ray crystallographic structures requires caution.

Conclusions:

• The conservation of allosteric mechanisms between LPYK and M1PYK is questionable.
• Further functional data is needed to definitively assess allosteric conservation.
• The relevance of native allosteric mechanisms to drug design warrants consideration.