In silico identification and characterization of the ion transport specificity for P-type ATPases in the Mycobacterium tuberculosis complex

Abstract

BackgroundP-type ATPases hydrolyze ATP and release energy that is used in the transport of ions against electrochemical gradients across plasma membranes, making these proteins essential for cell viability. Currently, the distribution and function of these ion transporters in mycobacteria are poorly understood.ResultsIn this study, probabilistic profiles were constructed based on hidden Markov models to identify and classify P-type ATPases in the Mycobacterium tuberculosis complex (MTBC) according to the type of ion transported across the plasma membrane. Topology, hydrophobicity profiles and conserved motifs were analyzed to correlate amino acid sequences of P-type ATPases and ion transport specificity. Twelve candidate P-type ATPases annotated in the M. tuberculosis H37Rv proteome were identified in all members of the MTBC, and probabilistic profiles classified them into one of the following three groups: heavy metal cation transporters, alkaline and alkaline earth metal cation transporters, and the beta subunit of a prokaryotic potassium pump. Interestingly, counterparts of the non-catalytic beta subunits of Hydrogen/Potassium and Sodium/Potassium P-type ATPases were not found.ConclusionsThe high content of heavy metal transporters found in the MTBC suggests that they could play an important role in the ability of M. tuberculosis to survive inside macrophages, where tubercle bacilli face high levels of toxic metals. Finally, the results obtained in this work provide a starting point for experimental studies that may elucidate the ion specificity of the MTBC P-type ATPases and their role in mycobacterial infections.

CtpB is a plasma membrane copper (I) transporting P-type ATPase of Mycobacterium tuberculosis

“…P-type ATPases may play an important role in mycobacterial ion homeostasis, since these usually transport cations against the concentration gradient [15]. M. tuberculosis has many P-type ATPases annotated as possible transporters of heavy-metal cations, suggesting that these proteins could play a relevant role in M. tuberculosis survival [16]. Some mycobacterial P 1B -type ATPases have been associated with bacterial detoxification of heavy metals cations, such as Cu + , Zn 2+ , Co 2+ , and Ni 2+ .…”

In silico approaches and chemical space of anti‐P‐type ATPase compounds for discovering new antituberculous drugs

“…In relation to mycobacteria, Mtb contains twelve open reading frames annotated as putative P‐type ATPases, which according to bioinformatics analyses, share at least 98% amino acid identity and can be classified as alkali/alkaline earth cation transporters (CtpE, CtpF, CtpH, and CtpI); potential heavy metal transporters (CtpA, CtpB, CtpC, CtpD, CtpJ, CtpV, and CtpG); and the K + transporter (P 1A type), KdpB . Interestingly, Mtb contains a high number of P‐type heavy metal ATPases compared to other bacteria . Among others, Mtb contains the heavy metal P‐type ATPases CtpA, CtpB, and CtpV, which are described as Cu + ‐ATPases (P 1B1 ‐type subfamily), in addition to CtpD and CtpJ which are reported as Co 2+ ‐ATPases (P 1B4 ‐type subfamily).…”

“…On the other hand, P‐type ATPases are membrane transporters that have a relevant role in Mtb virulence and survival. It is worth mentioning that Mtb contains a high number of heavy metal P‐type ATPases compared to other bacteria, suggesting that this type of transporters is also interesting anti‐TB targets . P‐type ATPases are involved in alkali/alkaline earth and heavy metal cation transport, generating electrochemical gradients that are necessary for ion homeostasis.…”

Mycobacterium tuberculosis and Copper: A Newly Appreciated Defense against an Old Foe?

“…All Ctp proteins are P-type ATPases, and there are 11 Ctp proteins in M. tuberculosis; although not all of them are regulated in a Cu-dependent manner, we cannot rule out that one or more of them function in Cu efflux. Interestingly, CtpA and CtpB are predicted to be Cu-binding ATPases, (25,26). If they do indeed bind Cu, it is possible these are required for metallating extra-cytoplasmic Cu-binding proteins.…”