Start: September 17, 2026 3:30 p.m.
End: September 17, 2026 4:30 p.m.
From Radicals to Redox: How Proteins Control Reactive Chemistry
Dr. Shiliang Tian
Assistant Professor, Department of Chemistry, Purdue University
Thursday, 09/17 @ 3:30 PM
FB 253
Biological systems routinely execute chemically difficult transformations by coupling metal-centered reactivity to precisely orchestrated protein dynamics. In this seminar, I will illustrate this principle through our work on two classes of metalloproteins in which protein motion and metal redox chemistry are tightly integrated to control high-energy intermediates. First, I will describe how large-scale conformational dynamics control radical initiation and selectivity in cobalamin-dependent mutases. Using an integrated cryo-EM and EPR approach, we resolved substrate-free and substrate-bound structures of lysine 5,6-aminomutase and ornithine 4,5-aminomutase, revealing an unprecedented ~65° domain rotation that translocates the cobalamin cofactor into the active site upon substrate binding. This domain alternation directly gates homolytic Co(III)–C bond cleavage and radical generation. In parallel, we identified an active-site hydrogen-bond network that confines the resulting 5′-deoxyadenosyl radical, enforcing productive hydrogen abstraction while suppressing off-pathway chemistry. Together, these findings provide a structural framework linking protein motion to metallocofactor activation and radical control. Second, I will show how a related integration of metal coordination, redox chemistry, and protein environment operates in human iron homeostasis. Specifically, I will discuss our discovery that the E2 domain of amyloid precursor protein (APP) functions as a redox-active copper metalloprotein involved in neuronal iron and oxidative homeostasis. Through EPR, EXAFS, and kinetic analyses, we showed that E2 harbors a dynamic Cu(I)/Cu(II) site capable of ferroxidase activity and rapid scavenging of reactive oxygen and nitrogen species, including superoxide and peroxynitrite. These findings redefine APP as an active participant in metal and redox regulation rather than solely a precursor to amyloid-β, and provide a molecular framework linking metal chemistry to neurodegenerative disease pathways.