My current interests centre on energy conversion in mammalian mitochondria. They include how the ATP synthase complex of 29 proteins of 15 different kinds is assembled with the participation of assembly factors, and how the enzymic activity of the enzyme and assembly intermediates is regulated. This regulation concerns a unidirectional inhibitor protein, IF1, which inhibits ATP hydrolysis only. Its inhibitory region is intrinsically disordered in solution and becomes progressively structured into an α-helix as it becomes entrapped in one of three catalytic interfaces of the enzyme. A related interest concerns the SLC25 family of inner mitochondrial membrane transport proteins, and one particular member, citrin, which exchanges internal aspartate for external glutamate. Citrin is an essential component of the urea cycle, which operates mainly in the liver. Mutations in human citrin are associated with a rare disease called citrin deficiency. One of our aims at the MRC Mitochondrial Biology Unit is to characterise cell-based and animal models of citrin deficiency.
My LMB interactions include my long-standing interest in Michel Goedert’s work on Alzheimer’s and with Lalita Ramakrishnan’s work on tuberculosis, originating in our studies on the structure of mycobacterial ATP synthase, the target of the antitubercular drug, bedaquiline.