Structure and Function of DsbA,a Key Bacterial Oxidative Folding Catalyst

Abstract

Since its discovery in 1991, the bacterial periplasmic oxidative folding catalyst DsbA has been the focus of intense research. Early studies addressed why it is so oxidizing and how it is maintained in its less stable oxidized state. The crystal structure of Escherichia coli DsbA (EcDsbA) revealed that the oxidizing periplasmic enzyme is a distant evolutionary cousin of the reducing cytoplasmic enzyme thioredoxin. Recent significant developments have deepened our understanding of DsbA function, mechanism, and interactions: the structure of the partner membrane protein EcDsbB, including its complex with EcDsbA, proved a landmark in the field. Studies of DsbA machineries from bacteria other than E. coli K-12 have highlighted dramatic differences from the model organism, including a striking divergence in redox parameters and surface features. Several DsbA structures have provided the first clues to its interaction with substrates, and finally, evidence for a central role of DsbA in bacterial virulence has been demonstrated in a range of organisms. Here, we review current knowledge on DsbA, a bacterial periplasmic protein that introduces disulfide bonds into diverse substrate proteins and which may one day be the target of a new class of anti-virulence drugs to treat bacterial infection. Antioxid. Redox Signal. 14, 1729–1760.

Introduction

• Nomenclature

Oxidative Protein Folding Pathways

• Eukaryotic pathways

• The classical bacterial dithiol oxidizing pathway: DsbA and DsbB

• The classical bacterial disulfide isomerization pathway

• Alternatives to the classical oxidative protein folding pathway

Structure of the Archetypal DsbA

• The Thioredoxin fold

• The inserted helical domain

• Invariant and highly conserved residues

• Structural features of the interaction with DsbB

• Structural implications for function

Variations to the Archetypal DsbA Fold

• DsbA structures from gamma-proteobacteria

• DsbA structures from bacteria with multiple DsbAs

• DsbA structures from Gram-positive bacteria

• Structures of other DsbA homologues

Ligand Binding by DsbA

• Identification of DsbA substrates

• DsbA structures with bound peptides

• DsbA structures with other bound ligands

• Common features of binding regions in DsbA homologues

Virulence-Associated Substrates of DsbA

• Chaperone-usher fimbriae

• Type 4 fimbriae

• Intimin, an outer membrane adhesin

• Flagella

• Toxins, secreted enzymes, and antimicrobial peptides

• Type III secretion

• Role of DsbA paralogues in bacterial pathogenesis

Conclusions and Perspectives