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, and many are chaparone proteins (Ellis-Guardiola et al. 2020). 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 Basigin-Tapasin-TREM2/PIGR Superfamily.

 

References:

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Lee, A., R.E. Westenbroek, F. Haeseleer, K. Palczewski, T. Scheuer, and W.A. Catterall. (2002). Differential modulation of Ca(v)2.1 channels by calmodulin and Ca2+-binding protein 1. Nat Neurosci 5: 210-217.

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Libé-Philippot, B., A. Lejeune, K. Wierda, N. Louros, E. Erkol, I. Vlaeminck, S. Beckers, V. Gaspariunaite, A. Bilheu, K. Konstantoulea, H. Nyitrai, M. De Vleeschouwer, K.M. Vennekens, N. Vidal, T.W. Bird, D.C. Soto, T. Jaspers, M. Dewilde, M.Y. Dennis, F. Rousseau, D. Comoletti, J. Schymkowitz, T. Theys, J. de Wit, and P. Vanderhaeghen. (2023). LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons. Cell 186: 5766-5783.e25.

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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.

Nagpal, K., T.S. Plantinga, J. Wong, B.G. Monks, N.J. Gay, M.G. Netea, K.A. Fitzgerald, and D.T. Golenbock. (2009). A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling. J. Biol. Chem. 284: 25742-25748.

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.

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.

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:.

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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.

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Examples:

TC#NameOrganismal TypeExample
8.A.43.1.1

The heme sequestration protein, Shr (Ouattara et al., 2010) (feeds iron into the Shp/SiaABC (HtsABC) ABC uptake system (3.A.1.14.10)).  The two NEAT domains are not equivalent (Ouattara et al. 2013).

Bacteria

Shr of Streptococcus pyogenes (B0LFQ8)

 
8.A.43.1.10

Amphoterin-induced protein 1, AMIGO-1, of 493 aas and 1 TMS.  May be involved in fasciculation as well as myelination of developing neural axons, and may also have a role in regeneration as well as neural plasticity in the adult nervous system. It is assembled with KCNB1 to modulate the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1. In mammalian brain neurons, AMIGO-1 is associated with Kv2 alpha subunits, and Kv2 alpha subunits are obligatory in determining the correct pattern of AMIGO-1 expression, plasma membrane trafficking and clustering (Bishop et al. 2018).

 

AMIGO-1 of Homo sapiens

 
8.A.43.1.11

Leucine-rich repeat transmembrane neuronal protein 1, LRRTM1 of 522 aas and 2 TMSs, N- and C-terminal.  It exhibits strong synaptogenic activity, and is restricted to excitatory presynaptic differentiation, acting at both pre- and postsynaptic levels.  It helps stabilize synaptic AMPA receptors at mature spines during basal synaptic transmission and LTP (Bhouri et al. 2018).

LRRTM1 of Homo sapiens

 
8.A.43.1.12

Internalin-A, InlA, of 800 aas and 2 TMSs, N- and C-terminal. L. monocytogenes virulence factors include two surface invasins, InlA and InlB, known to promote bacterial uptake by host cells, and the secreted pore-forming toxin listeriolysin O (LLO), which disrupts the phagosome to allow bacterial proliferation in the cytosol. No role for InlB was detected in any tested cells unless the InlB expression level was substantially enhanced, which was achieved by introducing a mutation (prfA*) in the gene encoding the transcription factor PrfA (Phelps et al. 2018). InlA and LLO were the most critical invasion factors. InlA facilitates both bacterial attachment and internalization in cells that express its receptor, E-cadherin. LLO promotes L. monocytogenes internalization into hepatocytes, but not into cytotrophoblasts and endothelial cells. LLO and InlA cooperate to increase the efficiency of host cell invasion by L. monocytogenes (Phelps et al. 2018).

InlA of Listeria monocytogenes

 
8.A.43.1.13

Leucine-rich repeat-containing protein 15, LRRC15 of 581 aas and 2 or 3 TMSs, one at the N-terminus and one or two at the C-terminus. LRRC15 is an essential regulator for osteogenesis of mesenchymal stem cells by modulating p65 cytoplasmic/nuclear translocation (Wang et al. 2018).

LRRC15 of Homo sapiens

 
8.A.43.1.14

Leucine-rich repeat-containing protein 26, LRRC26, of 334 aas.  Auxiliary protein of the large-conductance, voltage and calcium-activated potassium channel (BK alpha). LRRC26 is required for the conversion of BK alpha channels from a high-voltage to a low-voltage activated channel type in non-excitable cells. These are characterized by negative membrane voltages and constant low levels of calcium (Yan and Aldrich 2010; Yan and Aldrich 2012)High-resolution structures illuminate key principles underlying voltage and LRRC26 regulation of Slo1 channels (Kallure et al. 2023).

LRRC26 of Homo sapiens

 
8.A.43.1.15

Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1, LINGO1, of 620 aas with two TMSs, one N-terminal and one C-terminal. LINGO1 is a regulator of BK channels, which causes a "functional knockdown" of these currents and may contribute to the tremor associated with increased LINGO1 levels (Dudem et al. 2020).

LINGO1 of Homo sapiens

 
8.A.43.1.16

Toll-like receptor 2, TLR2 or TIL4,Lancioni et al. 2011 of 784 aas and 2 TMSs, N- and C-termnal.  It cooperates with TLR1 or TLR6 to mediate the innate immune response to bacterial lipoproteins or lipopeptides (Jin et al. 2007; Lancioni et al. 2011). It forms activation clusters composed of several receptors depending on the ligand. These clusters trigger signaling from the cell surface, and subsequently are targeted to the Golgi in a lipid-raft dependent pathway. It also forms the cluster TLR2:TLR6:CD14:CD36 in response to diacylated lipopeptides and TLR2:TLR1:CD14 in response to triacylated lipopeptides (Triantafilou et al. 2006). It is required for normal uptake of M. tuberculosis, a process that is inhibited by M. tuberculosis LppM. Receptor heterodimerization and co-receptor engagement in TLR2 activation is induced by MIC1 and MIC4 from Toxoplasma gondii (Costa Mendonça-Natividade et al. 2019). Association of TMED2 and TMED7 with TLRs facilitates anterograde transport from the ER to the Golgi (Holm et al. 2023).

 

TLR2 of Homo sapiens

 
8.A.43.1.17

CD14 of 375 aas and 2 TMSs, N- and C-terminal.  In concert with LBP, it binds to monomeric lipopolysaccharide and delivers it to the LY96/TLR4 complex, thereby mediating the innate immune response to bacterial lipopolysaccharide (LPS) (Kelley et al. 2013). It acts via MyD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (Haziot et al. 1996). It also acts as a coreceptor for the TLR2:TLR6 heterodimer in response to diacylated lipopeptides, and for the TLR2:TLR1 heterodimer in response to triacylated lipopeptides; these clusters trigger signaling from the cell surface and subsequently are targeted to the Golgi in a lipid-raft dependent pathway (Triantafilou et al. 2006). It binds electronegative LDL (LDL-) and mediates the cytokine release induced by LDL- (Estruch et al. 2013).

CD14 of Homo sapiens

 
8.A.43.1.18

Monocyte differentiation antigen CD14 of 483 aas and 2 TMSs, N- and C-terminal.

CD14 of Sparus aurata (gilthead seabream)

 
8.A.43.1.19

Monocyte differentiation antigen CD14 of 461 aas and 2 TMSs, N- and C-terminal.

CD14 of Alligator mississippiensis (American alligator)

 
8.A.43.1.2

Chlostridial Shr protein homologue

Firmicutes

Shr homologue of Clostridium botulinum

 
8.A.43.1.20

Leucine-rich repeat transmembrane neuronal protein 4, LRRTM4, of 590 aas and two TMSs, one at the N-terminus, and one near the C-terminus. It may play a role in the development and maintenance of the vertebrate nervous system. It exhibits strong synaptogenic activity but is restricted to excitatory presynaptic differentiation.  It is a member of the transsynaptic complex between rod photoreceptors and bipolar cells (Agosto and Wensel 2020).

LRRTM4 of Homo sapiens

 
8.A.43.1.21

Leucine-rich repeats and immunoglobulin-like domains protein 1, LRIG1, of 1093 aas. It consists of a signal peptide, 15 tandem leucine-rich repeats with cysteine-rich N- and C-flanking domains, three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tail (Guo et al. 2004). It acts as a feedback negative regulator of signaling by receptor tyrosine kinases, through a mechanism that involves enhancement of receptor ubiquitination and accelerated intracellular degradation (Gur et al. 2004). The functions of LRIG proteins in glioma have been reviewed (Mao et al. 2017).

LRIG1 of Homo sapiens

 
8.A.43.1.22

Toll/interleukin-1 receptor domain-containing adapter protein, TIRAP or MAL, of 221 aas. It is an adapter involved in TLR2 and TLR4 signaling pathways in the innate immune response. It acts via IRAK2 and TRAF-6, leading to the activation of NF-kappa-B and resulting in cytokine secretion and the inflammatory response (Nagpal et al. 2009). Toll-like receptors (TLRs) play an essential role in the detection and elimination of invading microbes. They are type-1 transmembrane receptors, containing extracellular leucine rich repeats and an intracellular TIR domain. Upon stimulation, these receptors interact with specific TIR domain-containing adaptor proteins. Five such adaptors are present in mammals (McGettrick and O'Neill 2004).

 

TIRAP of Homo sapiens

 
8.A.43.1.23

Kekkon-1, Kek-1 of 880 aas and 1 central TMS. It is a negative regulator of epidermal growth factor-activated receptor activity (Ghiglione et al. 2003).

Kek-1 of Drosophila melanogaster (Fruit fly)

 
8.A.43.1.24

Leucine-rich repeat-containing protein 4B, LRRC4B, of 713 aas amd 2 TMSs. one at the N-terminus, and one near the C-terminus. It is a synaptic adhesion protein that regulates the formation of excitatory synapses. The trans-synaptic adhesion between LRRC4B and PTPRF regulates the formation of excitatory synapses in a bidirectional manner. It may be a biomarkers for the diagnosis of encephalitis (Xiong et al. 2021).

 

LRRC4B of Homo sapiens

 
8.A.43.1.25

Toll-like receptor 1, TLR1, of 786 aas and 2 TMSs. Toll-like receptors (TLRs) comprise a family of transmembrane receptors whose signaling controls cellular processes of cell proliferation, survival, apoptosis, angiogenesis, remodeling, and repair of tissues. Polymorphisms in TLR genes can change the balance between pro and anti-inflammatory cytokines, modulating the risk of infection, chronic inflammation, and cancer (Quirino et al. 2021). TLR1 participates in the innate immune response to microbial agents, specifically recognizing diacylated and triacylated lipopeptides. It cooperates with TLR2 (TC# 8.A.43.1.16) to mediate the innate immune response to bacterial lipoproteins or lipopeptides (Lancioni et al. 2011), and it forms the activation cluster TLR2:TLR1:CD14 (CD14, TC# 8.A.43.1.17) in response to triacylated lipopeptides. This cluster triggers signaling from the cell surface and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (Triantafilou et al. 2006). Association of TMED2 and TMED7 with TLRs facilitates anterograde transport from the ER to the Golgi (Holm et al. 2023).

 

TLR1 of Homo sapiens

 
8.A.43.1.26

P-granule-associated novel protein 1, PAN1, a leucine-rich LRR-TM protein of 594 aas and 2 TMSs, one at the N-terminus and one near the C-terminus. It regulates diverse developmental processes including larval molting and gonad maturation (Gao et al. 2012; Gissendanner and Kelley 2013). The LRR-TM protein PAN-1 interacts with MYRF to promote its nuclear translocation in synaptic remodeling (Xia et al. 2021).

 

PAN1 of Caenorhabditis elegans

 
8.A.43.1.27

Leucine-rich repeat transmembrane protein, FLRT3, of 649 aas and 2 TMSs near the N- and C-termini of the protein. The protein mediates cell-cell contacts that promote an increase both in neurite number and in neurite length. It also plays a role in the regulation of the density of glutamaergic synapses (Lu et al. 2015). Variants can give rise to high myopia, an eye disorder (Swierkowska et al. 2021).  


FLRT3 of Homo sapiens

 
8.A.43.1.3

InlD protein of 567 aas and 2 TMSs

Firmicutes

InlD of Listeria monocytogenese

 
8.A.43.1.35

The Toll-like receptor 3, TLR3, of 904 aas and 2 TMSs, one N-terminal and one at about residue 350. A cryoEM structure is available (Cai et al. 2022).

TLR3 of Homo sapiens

 
8.A.43.1.36

Toll-like receptor 3, TLR3 of 911 aas and two TMSs, one at the N-terminus and one near the C-terminus at about residue 720. Its adaptor protein is the soluble TRIF (TIR-domain-containing adaptor-inducing interferon-beta) protein. The bioinformatics characteristics and expression of TLR3 and its adaptor protein TRIF in largemouth bass (Micropterus salmoides) upon Flavobacterium columnare infection has been described (Zhao et al. 2023).

TLR3 and TRIF of Micropterus salmoides (largemouth bass)

 
8.A.43.1.4

Toll9 of 576 aas and 2 TMSs

Animals

Toll9 of Anopheles gambiae

 
8.A.43.1.43

The LRRC37B protein of 947 aas with 2 TMSs, N- and C-terminal.  LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons (Libé-Philippot et al. 2023).

LRRC37B of Homo sapiens

 
8.A.43.1.5

Uncharacterized protein of 1349 aas and 2 TMSs.

Firmictues

UP of Listeria innocua

 
8.A.43.1.6

Uncharacterized protein of 425 aas and 2 TMSs

Animals

UP of Drosophila melanogaster

 
8.A.43.1.7

Uncharacterized protein of 1016 aas and 2 or 3 TMSs

Animals

UP of Branchiostoma floridae

 
8.A.43.1.8

Leucine-rich repeat-containing protein 55.  BK channel auxiliary gamma subunit LRRC55.  Auxiliary protein of the large-conductance, voltage and calcium-activated potassium channel (BK alpha; TC# 1.A.1.3.2). Modulates gating properties by producing a marked shift in the BK channel's voltage dependence of activation in the hyperpolarizing direction in the absence of calcium (Yan and Aldrich 2012). Only the transmembrane helix modulates channel activity (Li et al. 2016).

Animals

LRRC44 of Homo sapiens

 
8.A.43.1.9

Toll-like receptor 4, Tlr4, of 839 aas and 0 TMSs.  Mediates innate immune and inflamatory responses (Medzhitov et al. 1997). It forms a heterodimer with TLR6, which is rapidly internalized to trigger inflammatory responses (Estruch et al. 2013). Tmbim1 (TC# 1.A.14.3.10) promotes the lysosomal degradation of Tlr4 by cooperating with the ESCRT endosomal sorting complex to facilitate MVB formation, and the ubiquitination of Tmbim1 by the E3 ubiquitin ligase Nedd4l (Zhao et al. 2017).

 

Tlr4 of Homo sapiens

 
Examples:

TC#NameOrganismal TypeExample
8.A.43.2.1

TIR domain-containing adapter molecule 2, TICAM2 (TIRAP3, TIRP, TRAM) of 235 aas and 3 centrally located peaks of minor hydrophobicity that could be TMSs. It functions as sorting adapter in different signaling pathways to facilitate downstream signaling leading to type I interferon induction (Huai et al. 2015).

TICAM2 of Homo sapiens

 
8.A.43.2.2

TICAM2 of 243 aas and possibly two TMSs, N- and C-terminal.

TICAM2 of Branchiostoma lanceolatum

 
8.A.43.2.3

Uncharacterized protein of 497 aas and 0 TMSs.

UP of Asterias rubens (European starfish)

 
8.A.43.2.4

TIR domain-containing adapter molecule 1 of 696 aas and possibly one TMS at about residue 450.

Adapter of Nannospalax galili (Upper Galilee mountains blind mole rat)