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

[Image: see text] 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.