Crystal structures of AztD provide mechanistic insights into direct zinc transfer between proteins

Durga Prasad Neupane,Stephanie Hope Fullam,Erik Thomas Yukl,Kelly Natalia Chacón

doi:10.1038/s42003-019-0542-z

Durga Prasad Neupane, Stephanie Hope Fullam + Show 2 more

Open Access

https://doi.org/10.1038/s42003-019-0542-z

Copy DOI

Journal: Communications Biology	Publication Date: Aug 9, 2019
Citations: 7	License type: open-access

Affiliation: New Mexico State University, Reed College

Abstract

Zinc acquisition from limited environments is critical for bacterial survival and pathogenesis. AztD has been identified as a periplasmic or cell surface zinc-binding protein in numerous bacterial species. In Paracoccus denitrificans, AztD can transfer zinc directly to AztC, the solute binding protein for a zinc-specific ATP-binding cassette transporter system, suggesting a role in zinc acquisition and homeostasis. Here, we present the first cry\tstal structures of AztD from P. denitrificans and tbe human pathogen Citrobacter koseri, revealing a beta-propeller fold and two high-affinity zinc-binding sites that are highly conserved among AztD homologs. These structures combined with transfer assays using WT and mutant proteins provide rare insight into the mechanism of direct zinc transfer from one protein to another. Given the importance of zinc import to bacterial pathogenesis, these insights may prove valuable to the development of zinc transfer inhibitors as antibiotics.

Highlights

Zinc acquisition from limited environments is critical for bacterial survival and pathogenesis
Bacterial ATP-binding cassette (ABC) transporters are composed of a dimeric membrane permease and ATPase as well as a periplasmic (Gram-negative) or cell surface (Gram-positive) solute-binding protein (SBP)[7,8]
The bulk of sequences are found in Alphaproteobacteria and Gammaproteobacteria, which include P. denitrificans and C. koseri, respectively

Summary

Introduction

Zinc acquisition from limited environments is critical for bacterial survival and pathogenesis. We present the first cry stal structures of AztD from P. denitrificans and tbe human pathogen Citrobacter koseri, revealing a beta-propeller fold and two high-affinity zinc-binding sites that are highly conserved among AztD homologs. These structures combined with transfer assays using WT and mutant proteins provide rare insight into the mechanism of direct zinc transfer from one protein to another. The SBP confers high affinity and specificity to the system, and bacterial ABC transporters have been grouped according to the structure and substrate specificity of their SBPs9 By this designation, cluster A-I SBPs are specific for uncomplexed zinc, manganese, or iron. Inhibition of zinc binding or transfer from these proteins represents a promising target for the development of novel antimicrobials

Methods

Results

Conclusion