Insights on the Quest for the Structure–Function Relationship of the Mitochondrial Pyruvate Carrier
Brazilian Biosciences National Laboratory, Center for Research in Energy and Materials, Campinas 13083-970, Brazil
Postgraduate program in Biosciences and Technology of Bioactive Products, Institute of Biology, University of Campinas, Campinas 13083-970, Brazil
School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK
São Carlos Institute of Physics, University of São Paulo, São Carlos 13563-120, Brazil
Membrane Protein Laboratory, Diamond Light Source Limited, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK
Author to whom correspondence should be addressed.
Current address: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton 3800, Australia.
Current address: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin at Madison, Madison, WI 53705, USA.
Current address: National Physical Laboratory, Teddington, Middlesex TW11 0LW, UK.
Received: 16 October 2020 / Revised: 14 November 2020 / Accepted: 17 November 2020 / Published: 19 November 2020
The atomic structure of a biological macromolecule determines its function. Discovering how one or more amino acid chains fold and interact to form a protein complex is critical, from understanding the most fundamental cellular processes to developing new therapies. However, this is far from a straightforward task, especially when studying a membrane protein. The functional link between the oligomeric state and complex composition of the proteins involved in the active mitochondrial transport of cytosolic pyruvate is a decades-old question but remains urgent. We present a brief historical review beginning with the identification of the so-called mitochondrial pyruvate carrier (MPC) proteins, followed by a rigorous conceptual analysis of technical approaches in more recent biochemical studies that seek to isolate and reconstitute the functional MPC complex(es) in vitro. We correlate these studies with early kinetic observations and current experimental and computational knowledge to assess their main contributions, identify gaps, resolve ambiguities, and better define the research goal.