AAA+ Molecular Chaperone ClpB in Leptospira interrogans: Its Role and Significance in Leptospiral Virulence and Pathogenesis of Leptospirosis

Abstract

Bacterial ClpB is an ATP-dependent disaggregase that belongs to the Hsp100/Clp subfamily of the AAA+ ATPases and cooperates with the DnaK chaperone system in the reactivation of aggregated proteins, as well as promotes bacterial survival under adverse environmental conditions, including thermal and oxidative stresses. In addition, extensive evidence indicates that ClpB supports the virulence of numerous bacteria, including pathogenic spirochaete Leptospira interrogans responsible for leptospirosis in animals and humans. However, the specific function of ClpB in leptospiral virulence still remains to be fully elucidated. Interestingly, ClpB was predicted as one of the L. interrogans hub proteins interacting with human proteins, and pathogen-host protein interactions are fundamental for successful invasion of the host immune system by bacteria. The aim of this review is to discuss the most important aspects of ClpB's function in L. interrogans, including contribution of ClpB to leptospiral virulence and pathogenesis of leptospirosis, a zoonotic disease with a significant impact on public health worldwide.

Keywords: ClpB; Leptospira; leptospirosis; molecular chaperone; pathogen–host interactions; virulence factors.

Figure 1

Domain organization of the ClpB monomer [based on 61]. The monomer is composed of the following domains: N-terminal domain (ND), nucleotide-binding domain 1 (NBD-1), middle domain (MD), and nucleotide-binding domain 2 (NBD-2). All characteristic and conserved motifs of the AAA+ ATPases coordinating ATP binding and hydrolysis, such as the Walker A: GX₄GKT/S (A), Walker B: Hy₂DE (B), sensor 1, sensor 2 (GAR), and the arginine fingers (R), are also indicated.

Figure 2

Functional classification of putative protein substrates of L. interrogans ClpB. The pie chart was created using the OriginLab software (OriginPro2016, Northampton, MA, USA) and shows the percentage distribution of the identified ClpB-interacting proteins among different biological processes [70].

Figure 3

The most important potential ClpB–human proteins interactions and their possible role during leptospiral infections [72].