Biophysical Chemistry of Zinc Homeostasis in the Human Pathogen Streptococcus pneumoniae

• Main Author: Huerta, Fidel
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2020
• Subjects: Biochemistry; Microbiology; Pathology
• ISBN: 9798691284410

ZnII homeostasis is important for S. pneumoniae colonization of the upper respiratory tract and migration to sites of infection as zinc availability changes as a function of host microenvironmental niche and the innate immune response. ZnII uptake in streptococci is governed by the adcRBCA operon, which encodes the multi-subunit ATPbinding cassette (ABC) transporter, AdcBCA, that brings ZnII into the cell, and the ZnII uptake repressor, termed AdcR (adhesin competence repressor). AdcR is a member of the ≈16,000-member, multiple antibiotic resistance repressor (MarR) family of proteins. AdcR is of interest since it is the only member of the MarR family in which the inducer functions as an allosteric activator, rather than inhibitor, of DNA operator binding. The regulation of protein function is governed by a principle known as allostery or “action at a distance” by which function, often catalysis, is modulated through ligand binding to a site distinct from the “active site”. Recent studies have shown that allostery can occur through little or no perturbation of structure, hence, static structures often lack sufficient insights required to obtain a comprehensive understanding of a allosteric response mechanism. There is a long-standing interest in the underlying mechanisms of such “action at a distance” processes, particularly in the context of bacterial transition metal homeostasis and sensing. Using state-of-the-art biomolecular NMR spectroscopy shows allostery can be derive almost exclusively from perturbations of internal motions within proteins, with minimal structural change between states. Such an “entropically-driven” allosteric model contrasts sharply with the concept of a physical “allosteric pathway” or “molecular wire” on which internal motions must propagate. Current work shows allosteric response can be governed solely by ligand-mediated perturbations of conformational entropy as a sole or principle cause of an allosteric response as we show with the binding of ZnII to AdcR.