Correlation of Conservation of Sequence and Structures of Mycobacterial Hemerythrin-like Proteins with Evolutionary Relationship and Host Pathogenicity

Abstract

The Rv2633c gene of Mycobacterium tuberculosis , which plays a role in infection, encodes a hemerythrin-like protein (HLP). The crystal structure of an orthologue of Rv2633c, the HLP from Mycobacterium kansasii , revealed that it possessed structural features that were distinct from other hemerythrins and HLPs. These and other orthologous proteins comprise a distinct class of non-heme di-iron HLPs that are only found in mycobacteria. This study presents an analysis and comparison of protein sequences, putative structures, and evolutionary relationship of HLPs from 20 mycobacterial species that are known to cause tuberculosis or pulmonary disorders in humans. The results of this analysis allowed correlation of the physicochemical characteristics of amino acid residues that are substituted in these highly conserved sequences with their position in structures, possible effects on function, and evolutionary relationships. The sequences of the proteins from M. tuberculosis , Mycobacterium bovis, and other members of the M. tuberculosis complex, which cause tuberculosis, have substitutions not seen in the other non-tuberculous mycobacteria. Furthermore, groups of species that are closely related, based on phylogenetic analysis, possess substitutions of otherwise conserved residues not seen in other species that are less related. This information is correlated with the occurrence and clinical presentations of these groups of mycobacterial species. The results of this study provide a framework for structure–function studies to determine how subtle differences in the primary sequences of members of this family of proteins correlate with their structures and activities and how this may influence the infectious properties of the host species.

The hemerythrin-like diiron protein from Mycobacterium kansasii is a nitric oxide peroxidase

“…These unusual properties of the Mka HLP are likely related the nature of the amino acid side-chains that coordinate the two irons and their geometry. This combination of amino acid residue ligands is unique to mycobacterial HLPs (1,7). This information points to a novel mechanism for the catalysis of the peroxidase reaction by a diiron center.…”

“…The use of a tyrosine ligand and the pattern of amino acid ligation are conserved among the mycobacterial J o u r n a l P r e -p r o o f HLPs. These features are not seen in hemerythrins or HLPs from any others (1,7). A bridging solvent molecule completes the coordination.…”

“…Certain mycobacteria possess oxo-bridged diiron proteins with active site features similar to those of hemerythrin (1). These are a distinct class of hemerythrin-like proteins (HLPs) that are found in mycobacterial species that cause respiratory disorders in humans.…”

“…The structure of the Mka HLP (4) shows it to be a monomer comprised of a similar four helix bundle with an additional fifth helix (Figure 1A). The oxo-bridged diiron site in the mycobacterial HLPs are coordinated by the side chains of six amino acids; four histidines, two glutamic acids and a tyrosine (1,4) (Figure 1B). The use of a tyrosine ligand and the pattern of amino acid ligation are conserved among the mycobacterial J o u r n a l P r e -p r o o f HLPs.…”

Fingolimod synergizes and reverses K. pneumoniae resistance to colistin

“…Typically, the sequence identity, QMEANDisCo, and GMQE scale range from 0 to 1 to indicate the credibility of the model reliability ( Ma et al, 2020 ). The model result was seen in Figure 5A .…”