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8.A.43 The NEAT-domain containing methaemoglobin heme sequestration (N-MHS) Family

Surface or secreted proteins with NEA-Transporter (NEAT) domains play a central role in haem acquisition and trafficking across the cell envelope of Gram-positive bacteria. Group A Streptococcus (GAS), a β-haemolytic human pathogen, expresses a NEAT protein, Shr, which binds several haemoproteins and extracellular matrix (ECM) components. Shr is a complex, membrane-anchored protein, with a unique N-terminal domain (NTD) and two NEAT domains separated by a central leucine-rich repeat region. Ouattara et al. (2010) carried out analyses of the functional domains in Shr. They showed that Shr obtains haem in solution and reduces the haem iron. Both of the constituent NEAT domains of Shr are responsible for binding haem, although they are missing a critical tyrosine residue found in the ligand-binding pockets of other haem-binding NEAT domains. A region within the Shr NTD interacts with methaemoglobin. Shr NEAT domains, however, do not contribute significantly to the binding of methaemoglobin but mediate binding to the ECM components fibronectin and laminin. A protein fragment containing the NTD plus the first NEAT domain was found to be sufficient to sequester haem directly from methaemoglobin. Correlating these in vitro findings to in vivo biological function, mutant analysis established the role of Shr in GAS growth with methaemoglobin as a sole source of iron, and indicates that at least one NEAT domain is necessary for the utilization of methaemoglobin. Outtara et al. (2010) suggested that Shr is the prototype of a new group of NEAT composite proteins involved in haem uptake found in Pyogenic streptococci and Clostridium novyi.

The hemolytic Group A Streptococcus (GAS) possesses the Shr protein which as noted above, participates in iron acquisition by obtaining heme from host hemoglobin and delivering it to the adjacent receptor on the surface, Shp. Heme is then conveyed to the SiaABC proteins (TC# 3.A.1.14.10) for transport across the membrane. Using rapid kinetic studies, Ouattara et al. (2013) investigated the role of the two heme binding NEAT modules of Shr. Stopped-flow analysis showed that holoNEAT1 quickly delivered heme to apoShp. HoloNEAT2 did not exhibit such activity; only little and slow transfer of heme from NEAT2 to apoShp was seen, suggesting that Shr NEAT domains have distinctive roles in heme transport. HoloNEAT1 also provided heme to apoNEAT2 by a fast and reversible process, the first transfer observed between isolated NEAT domains of the same receptor. Sequence alignment revealed that Shr NEAT domains belong to two families of NEAT domains that are conserved in Shr orthologs from several species. Based on the heme transfer kinetics, Shr proteins may modulate heme uptake according to heme availability by a mechanism where NEAT1 facilitates fast heme delivery to Shp, whereas NEAT2 serves as a temporary storage for heme on the bacterial surface (Ouattara et al., 2013).

Toll-like receptors (TLRs) control immune functions. Vidya et al. 2017 reviewed their significance, function, regulation and expression patterns. The tripartite TLRs are type I integral transmembrane receptors that are involved in recognition and conveying of pathogens to the immune system. These paralogs are located on cell surfaces or within endosomes. The TLRs are found to be functionally involved in the recognition of self and non-self-antigens, maturation of DCs and initiation of antigen-specific adaptive immune responses as they bridge innate and adaptive immunity. They also play a role in immunotherapy and vaccination. Signals generated by TLRs are transduced through NFkappaB signaling and MAP kinases to recruit pro-inflammatory cytokines and co-stimulatory molecules, which promote inflammatory responses. The excess production of these cytokines leads to grave systemic disorders like tumor growth and autoimmune disorders (Vidya et al. 2017). 

This family belongs to the: Leucine-rich Repeat-containing Domain.

References associated with 8.A.43 family:

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Li, Q., X. Guan, K. Yen, J. Zhang, and J. Yan. (2016). The single transmembrane segment determines the modulatory function of the BK channel auxiliary γ subunit. J Gen Physiol 147: 337-351. 27022192
Medzhitov, R., P. Preston-Hurlburt, and C.A. Janeway, Jr. (1997). A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388: 394-397. 9237759
Ouattara, M., A. Pennati, D.J. Devlin, Y.S. Huang, G. Gadda, and Z. Eichenbaum. (2013). Kinetics of heme transfer by the Shr NEAT domains of Group A Streptococcus. Arch Biochem Biophys 538: 71-79. 23993953
Ouattara, M., E.B. Cunha, X. Li, Y.S. Huang, D. Dixon, and Z. Eichenbaum. (2010). Shr of group A streptococcus is a new type of composite NEAT protein involved in sequestering haem from methaemoglobin. Mol. Microbiol. 78: 739-756. 20807204
Phelps, C.C., S. Vadia, E. Arnett, Y. Tan, X. Zhang, S. Pathak-Sharma, M.A. Gavrilin, and S. Seveau. (2018). Relative Roles of Listeriolysin O, InlA, and InlB in Listeria monocytogenes Uptake by Host Cells. Infect. Immun. 86:. 30061379
Vidya, M.K., V.G. Kumar, V. Sejian, M. Bagath, G. Krishnan, and R. Bhatta. (2017). Toll-like receptors: Significance, ligands, signaling pathways, and functions in mammals. Int Rev Immunol 1-17. [Epub: Ahead of Print] 29028369
Wang, Y., Y. Liu, M. Zhang, L. Lv, X. Zhang, P. Zhang, and Y. Zhou. (2018). LRRC15 promotes osteogenic differentiation of mesenchymal stem cells by modulating p65 cytoplasmic/nuclear translocation. Stem Cell Res Ther 9: 65. 29523191
Yan, J. and R.W. Aldrich. (2010). LRRC26 auxiliary protein allows BK channel activation at resting voltage without calcium. Nature 466: 513-516. 20613726
Yan, J. and R.W. Aldrich. (2012). BK potassium channel modulation by leucine-rich repeat-containing proteins. Proc. Natl. Acad. Sci. USA 109: 7917-7922. 22547800
Zhao, G.N., P. Zhang, J. Gong, X.J. Zhang, P.X. Wang, M. Yin, Z. Jiang, L.J. Shen, Y.X. Ji, J. Tong, Y. Wang, Q.F. Wei, Y. Wang, X.Y. Zhu, X. Zhang, J. Fang, Q. Xie, Z.G. She, Z. Wang, Z. Huang, and H. Li. (2017). Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4. Nat. Med. 23: 742-752. 28481357