Skip to Main Content

Dr. Elizabeth Nolan

Massachusetts Institute of Technology;

October 13th, 2017 – Fall Seminar

Time and Location: Noon in Meyerhoff Chemistry, Room 120

Host: Dr. Aaron Smith 

Metals and Immunity

Abstract:

The global public health problems of infectious disease and antibiotic resistance motivate our
bioinorganic investigations of the host/pathogen interaction. Metal ions are essential nutrients for
all organisms, and metal-ion withholding is one accepted mechanism of innate immunity. Inspired
by the structures and biological functions of human host-defense proteins that participate in this
metal-ion withholding response, we aim to achieve molecular-level and quantitative depictions of
how these biomolecules contribute to innate immunity, metal homeostasis, and physiology. In one
thrust, we are investigating the metal-sequestering antimicrobial protein calprotectin. This host-
defense protein is released by neutrophils and epithelial cells, and exerts antimicrobial activity
attributed to its ability to sequester transition metals from microbes. Our central hypotheses are
that calprotectin (i) contributes to human physiology in multiple contexts, (ii) responds to local
environmental stimuli and thereby exists in multiple structural forms that have particular
physiological roles, and (iii) participates in the homeostasis of metals in broad terms. Here, we
describe our bioinorganic studies of human calprotectin, which reveal remarkable biological
coordination chemistry essential for its function as an antimicrobial agent. Each calprotectin
heterodimer exhibits six distinct metal-binding sites, and we report our discovery that calprotectin
employs Ca(II) ions to tune its affinity for first-row transition metal ions. This mechanism allows
for calprotectin to switch between relatively low and high affinity forms, and effectively turn on
its metal-sequestering function in the extracellular space where Ca(II) levels are high. We also
focus on our studies of Fe(II) chelation by calprotectin, which suggest that this protein has the
capacity to contribute to iron homeostasis under reducing and anaerobic conditions where iron
persists in the ferrous oxidation state.