Type 1 periplasmic binding fold superfamily; Type 1 periplasmic binding fold superfamily. This model and hierarchy represent the ligand binding domains of the LacI family of transcriptional regulators, periplasmic binding proteins of the ABC-type transport systems, the family C G-protein couples receptors (GPCRs), membrane bound guanylyl cyclases including the family of natriuretic peptide receptors (NPRs), and the N-terminal leucine-isoleucine-valine binding protein (LIVBP)-like domains of the ionotropic glutamate receptors (iGluRs). In LacI-like transcriptional regulator and the bacterial periplasmic binding proteins, the ligands are monosaccharides, including lactose, ribose, fructose, xylose, arabinose, galactose/glucose and other sugars, with a few exceptions. Periplasmic sugar binding proteins are one of the components of ABC transporters and are involved in the active transport of water-soluble ligands. The LacI family of proteins consists of transcriptional regulators related to the lac repressor. In this case, the sugar binding domain binds a sugar which changes the DNA binding activity of the repressor domain. The periplasmic binding proteins are the primary receptors for chemotaxis and transport of many sugar based solutes. The core structures of periplasmic binding proteins are classified into two types, and they differ in number and order of beta strands: type 1 has six beta strands while type 2 has five beta strands per sub-domain. These two structural folds are thought to be distantly related via a common ancestor. Notably, while the N-terminal LIVBP-like domain of iGluRs belongs to the type 1 periplasmic-binding fold protein superfamily, the glutamate-binding domain of the iGluR is structurally similar to the type 2 periplasmic-binding fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  15 QTLVIMCASSDTIRSIMLVAHRHGMTSGDYAFFNIELFNSSSYGDGSWKRGDKHDFEAKQAYSSLQTVTLLRTVKPEFEK 94
Cdd:cd06386   200 ERVVIMCASSDTIRSIMLVAHRHGMTNGDYAFFNIELFNSSSYGNGSWKRGDKHDFEAKQAYSSLQTVTLLRTVKPEFEK 279

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  95 FSMEVKSSVEKQGLNMEDYVNMFVEGFHDAILLYVLALHEVLRAGYSKKDGGKIIQQTWNRTFEGIAGQVSIDANGDRYG 174
Cdd:cd06386   280 FSMEVKSSVQKQGLNDEDYVNMFVEGFHDAILLYALALHEVLRNGYSKKDGGKIIQQTWNRTFEGIAGQVSIDANGDRYG 359

                         170       180       190
                  ....*....|....*....|....*....|..
gi 1402624253 175 DFSVIAMTDVEAGTQEVIGDYFGKEGRFEMRP 206
Cdd:cd06386   360 DFSVIAMTDVEAGTQEVIGDYFGKEGRFEMRP 391

ligand-binding domain of type C natriuretic peptide receptor; Ligand-binding domain of type C natriuretic peptide receptor (NPR-C). NPR-C is found in atrial, mesentery, placenta, lung, kidney, venous tissue, aortic smooth muscle, and aortic endothelial cells. The affinity of NPR-C for natriuretic peptides is ANP>CNP>BNP. The extracellular domain of NPR-C is about 30% identical to NPR-A and NPR-B. However, unlike the cyclase-linked receptors, it contains only 37 intracellular amino acids and no guanylyl cyclase activity. Major function of NPR-C is to clear natriuretic peptides from the circulation or extracellular surroundings through constitutive receptor-mediated internalization and degradation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  15 QTLVIMCASSDTIRSIMLVAHRHGMTSGDYAFFNIELFNSSSYGDGSWKRGDKHDFEAKQAYSSLQTVTLLRTVKPEFEK 94
Cdd:cd06386   200 ERVVIMCASSDTIRSIMLVAHRHGMTNGDYAFFNIELFNSSSYGNGSWKRGDKHDFEAKQAYSSLQTVTLLRTVKPEFEK 279

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  95 FSMEVKSSVEKQGLNMEDYVNMFVEGFHDAILLYVLALHEVLRAGYSKKDGGKIIQQTWNRTFEGIAGQVSIDANGDRYG 174
Cdd:cd06386   280 FSMEVKSSVQKQGLNDEDYVNMFVEGFHDAILLYALALHEVLRNGYSKKDGGKIIQQTWNRTFEGIAGQVSIDANGDRYG 359

                         170       180       190
                  ....*....|....*....|....*....|..
gi 1402624253 175 DFSVIAMTDVEAGTQEVIGDYFGKEGRFEMRP 206
Cdd:cd06386   360 DFSVIAMTDVEAGTQEVIGDYFGKEGRFEMRP 391

Transmembrane domain of Ephrin Receptor A1 Protein Tyrosine Kinase; Ephrin receptors (EphRs) comprise the largest subfamily of receptor PTKs, and are classified into two classes (EphA and EphB), corresponding to binding preferences for either GPI-anchored ephrin-A ligands or transmembrane ephrin-B ligands. Vertebrates have ten EphA and six EphB receptors, which display promiscuous ligand interactions within each class. EphA1 has been associated with late-onset Alzheimer's disease and certain cancers such as colorectal and gastric carcinomas. EphRs contain an ephrin binding domain and two fibronectin repeats extracellularly, a single-span transmembrane (TM) domain, and a cytoplasmic tyr kinase domain. Binding of the ephrin ligand to EphR requires cell-cell contact since both are anchored to the plasma membrane. This allows ephrin/EphR dimers to form, leading to the activation of the intracellular tyr kinase domain. The resulting downstream signals occur bidirectionally in both EphR-expressing cells (forward signaling) and ephrin-expressing cells (reverse signaling). The main effect of ephrin/EphR interaction is cell-cell repulsion or adhesion. Ephrin/EphR signaling is important in neural development and plasticity, cell morphogenesis and proliferation, cell-fate determination, embryonic development, tissue patterning, and angiogenesis. The TM domain mediates dimerization.

                          10        20        30
                  ....*....|....*....|....*....|..
gi 1402624253 236 SGGLEESAVTGIVVGALLGAGLLMAFYFFRKK 267
Cdd:cd12841     5 SRGLTGGEIVAIIFGLLLGVALLLGILVFRSR 36

ligand-binding domain of type C natriuretic peptide receptor; Ligand-binding domain of type C natriuretic peptide receptor (NPR-C). NPR-C is found in atrial, mesentery, placenta, lung, kidney, venous tissue, aortic smooth muscle, and aortic endothelial cells. The affinity of NPR-C for natriuretic peptides is ANP>CNP>BNP. The extracellular domain of NPR-C is about 30% identical to NPR-A and NPR-B. However, unlike the cyclase-linked receptors, it contains only 37 intracellular amino acids and no guanylyl cyclase activity. Major function of NPR-C is to clear natriuretic peptides from the circulation or extracellular surroundings through constitutive receptor-mediated internalization and degradation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  15 QTLVIMCASSDTIRSIMLVAHRHGMTSGDYAFFNIELFNSSSYGDGSWKRGDKHDFEAKQAYSSLQTVTLLRTVKPEFEK 94
Cdd:cd06386   200 ERVVIMCASSDTIRSIMLVAHRHGMTNGDYAFFNIELFNSSSYGNGSWKRGDKHDFEAKQAYSSLQTVTLLRTVKPEFEK 279

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  95 FSMEVKSSVEKQGLNMEDYVNMFVEGFHDAILLYVLALHEVLRAGYSKKDGGKIIQQTWNRTFEGIAGQVSIDANGDRYG 174
Cdd:cd06386   280 FSMEVKSSVQKQGLNDEDYVNMFVEGFHDAILLYALALHEVLRNGYSKKDGGKIIQQTWNRTFEGIAGQVSIDANGDRYG 359

                         170       180       190
                  ....*....|....*....|....*....|..
gi 1402624253 175 DFSVIAMTDVEAGTQEVIGDYFGKEGRFEMRP 206
Cdd:cd06386   360 DFSVIAMTDVEAGTQEVIGDYFGKEGRFEMRP 391

ligand-binding domain of membrane guanylyl-cyclase receptors; Ligand-binding domain of membrane guanylyl-cyclase receptors. Membrane guanylyl cyclases (GC) have a single membrane-spanning region and are activated by endogenous and exogenous peptides. This family can be divided into three major subfamilies: the natriuretic peptide receptors (NPRs), sensory organ-specific membrane GCs, and the enterotoxin/guanylin receptors. The binding of peptide ligands to the receptor results in the activation of the cytosolic catalytic domain. Three types of NPRs have been cloned from mammalian tissues: NPR-A/GC-A, NPR-B/ GC-B, and NPR-C. In addition, two of the GCs, GC-D and GC-G, appear to be pseudogenes in humans. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are produced in the heart, and both bind to the NPR-A. NPR-C, also termed the clearance receptor, binds each of the natriuretic peptides and can alter circulating levels of these peptides. The ligand binding domain of the NPRs exhibits strong structural similarity to the type 1 periplasmic binding fold protein family.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  18 VIMCASSDTIRSIMLVAHRHGMTSGDYAFFNIELFNSSSYGDGS--WKRGDKHDFEAKQAYSSLQTVTLLRTVKPEFEKF 95
Cdd:cd06352   199 IVLCFDSETVRQFMLAAHDLGMTNGEYVFIFIELFKDGFGGNSTdgWERNDGRDEDAKQAYESLLVISLSRPSNPEYDNF 278

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  96 SMEVKSSVEKQGLNM----EDYVNMFVEGFHDAILLYVLALHEVLRAGYSKKDGGKIIQQTWNRTFEGIAGQVSIDANGD 171
Cdd:cd06352   279 SKEVKARAKEPPFYCydasEEEVSPYAAALYDAVYLYALALNETLAEGGNYRNGTAIAQRMWNRTFQGITGPVTIDSNGD 358

                         170       180
                  ....*....|....*....|....*.
gi 1402624253 172 RYGDFSVIAMtDVEAGTQEVIGDYFG 197
Cdd:cd06352   359 RDPDYALLDL-DPSTGKFVVVLTYDG 383

ligand-binding domain of family C G-protein couples receptors (GPCRs), membrane bound guanylyl cyclases such as natriuretic peptide receptors (NPRs), and N-terminal leucine/isoleucine/valine-binding protein (LIVBP)-like domain of ionotropic glutamate rece; This CD represents the ligand-binding domain of the family C G-protein couples receptors (GPCRs), membrane bound guanylyl cyclases such as the family of natriuretic peptide receptors (NPRs), and the N-terminal leucine-isoleucine-valine binding protein (LIVBP)-like domain of the ionotropic glutamate receptors, all of which are structurally similar and related to the periplasmic-binding fold type 1 family. The family C GPCRs consists of metabotropic glutamate receptor (mGluR), a calcium-sensing receptor (CaSR), gamma-aminobutyric acid receptor (GABAbR), the promiscuous L-alpha-amino acid receptor GPR6A, families of taste and pheromone receptors, and orphan receptors. Truncated splicing variants of the orphan receptors are not included in this CD. The family C GPCRs are activated by endogenous agonists such as amino acids, ions, and sugar based molecules. Their amino terminal ligand-binding region is homologous to the bacterial leucine-isoleucine-valine binding protein (LIVBP) and a leucine binding protein (LBP). The ionotropic glutamate receptors (iGluRs) have an integral ion channel and are subdivided into three major groups based on their pharmacology and structural similarities: NMDA receptors, AMPA receptors, and kainate receptors. The family of membrane bound guanylyl cyclases is further divided into three subfamilies: the ANP receptor (GC-A)/C-type natriuretic peptide receptor (GC-B), the heat-stable enterotoxin receptor (GC-C)/sensory organ specific membrane GCs such as retinal receptors (GC-E, GC-F), and olfactory receptors (GC-D and GC-G).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  18 VIMCASSDTIRSIMLVAHRHGMTSGDYAFFNIELFNSSSygdgswkrgDKHDFEAKQAYSSLQTVTLLRTVKPEFEKFSM 97
Cdd:cd06269   196 IILLASPDTARSLMLEAKRLDMTSKDYVWFVIDGEASSS---------DEHGDEARQAAEGAITVTLIFPVVKEFLKFSM 266

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  98 EVK--SSVEKQGLNMEDYVNMFVEGFHDAILLyvlalhevlragyskkdggkiiqqtwnrtfegiagqvsidangDRYGD 175
Cdd:cd06269   267 ELKlkSSKRKQGLNEEYELNNFAAFFYDAVLA-------------------------------------------DRPGQ 303

                         170       180       190
                  ....*....|....*....|....*....|
gi 1402624253 176 FSVIAMTDVEAGTQEVIGDYFGkEGRFEMR 205
Cdd:cd06269   304 FSIINLQYTEAGDYRKVGTWDS-EGGLNMS 332

Ligand-binding domain of membrane bound guanylyl cyclases; Ligand-binding domain of membrane bound guanylyl cyclases (GCs), which are known to be activated by sperm-activating peptides (SAPs), such as speract or resact. These ligand peptides are released by a range of invertebrates to stimulate the metabolism and motility of spermatozoa and are also potent chemoattractants. These GCs contain a single transmembrane segment, an extracellular ligand binding domain, and intracellular protein kinase-like and cyclase catalytic domains. GCs of insect and nematodes, which exhibit high sequence similarity to the speract receptor are also included in this model.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  18 VIMCASSDTIRSIMLVAHRHGMT-SGDYAF--FNIELFNSSSYGDGSWKRGDKHDF----EAKQAYSSLQTVTLLRTVKP 90
Cdd:cd06370   202 YVFLGDYSLLREFMYYAEDLGLLdNGDYVVigVELDQYDVDDPAKYPNFLSGDYTKndtkEALEAFRSVLIVTPSPPTNP 281

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  91 EFEKFSMEVKSSVEKQGLNMEDY--------VNMFVEGFHDAILLYVLALHEVLRAGYSKKDGGKIIQQTWNRTFEGIAG 162
Cdd:cd06370   282 EYEKFTKKVKEYNKLPPFNFPNPegiektkeVPIYAAYLYDAVMLYARALNETLAEGGDPRDGTAIISKIRNRTYESIQG 361

                         170       180
                  ....*....|....*....|....*..
gi 1402624253 163 -QVSIDANGDRYGDFSVIAMTDVEAGT 188
Cdd:cd06370   362 fDVYIDENGDAEGNYTLLALKPNKGTN 388

Ligand-binding domain of membrane guanylyl cyclase G; This group includes the ligand-binding domain of membrane guanylyl cyclase G (GC-G) which is a sperm surface receptor and might function, similar to its sea urchin counterpart, in the early signaling event that regulates the Ca2+ influx/efflux and subsequent motility response in sperm. GC-G appears to be a pseudogene in human. Furthermore, in contrast to the other orphan receptor GCs, GC-G has a broad tissue distribution in rat, including lung, intestine, kidney, and skeletal muscle.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  17 LVIMCASSDTiRSIMLVAHRHGMTSGDYAFFNIELFNsssygDGSWKR--GDKHDFEAKQAYSSLQTVTLLRTVKPEFEK 94
Cdd:cd06372   200 IVLICSSEDA-RSILLEAEKLGLMDGEYVFFLLQQFE-----DSFWKEvlNDEKNQVFLKAYEMVFLIAQSSYGTYGYSD 273

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  95 FSMEVKSSVEKQ----GLNMEDYVNMFVEGFHDAILLYVLALHEVLRAGYSKKDGGKIIQQTWNR---TFEGIAGQVSID 167
Cdd:cd06372   274 FRKQVHQKLRRApfysSISSEDQVSPYSAYLHDAVLLYAMGLKEMLKDGKDPRDGRALLQTLRGYnqtTFYGITGLVYLD 353

                         170
                  ....*....|....
gi 1402624253 168 ANGDRYGDFSVIAM 181
Cdd:cd06372   354 VQGERHMDYSVYDL 367

ligand-binding domain of membrane guanylyl cyclases (GC-D, GC-E, and GC-F) that are specifically expressed in sensory tissues; This group includes the ligand-binding domain of membrane guanylyl cyclases (GC-D, GC-E, and GC-F) that are specifically expressed in sensory tissues. They share a similar topology with an N-terminal extracellular ligand-binding domain, a single transmembrane domain, and a C-terminal cytosolic region that contains kinase-like and catalytic domains. GC-D is specifically expressed in a subpopulation of olfactory sensory neurons. GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have important roles in phototransduction. Unlike the other family members, GC-E and GC-F have no known extracellular ligands. Instead, they are activated under low calcium conditions by guanylyl cyclase activating proteins called GCAPs. GC-D expressing neurons have been implicated in pheromone detection and GC-D is phylogenetically more similar to the Ca2+-regulated GC-E and GC-F than to receptor GC-A, -B and -C which are activated by peptide ligands. Moreover, these olfactory GCs and retinal GCs share characteristic sequence similarity in a regulatory domain that is involved in the binding of GCAPs, suggesting GC-D activity may be regulated by an unknown extracellular ligand and intracellular Ca2+. Rodent GC-D-expressing neurons have been implicated in pheromone detection and were recently shown to respond to atmospheric CO2 which is an olfactory stimulus for many invertebrates and regulates some insect innate behavior, such as the location of food and hosts.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  17 LVIMCASSDTI-----RSIMLVAHRHGMTSGDYAFFNIE-LFNSSSYGDGSWKRGDKhDFEAKQAYSSLQTVTLLRTVKP 90
Cdd:cd06371   188 VVIMCMHSVLIggeeqRTLLEAAHDMGLTDGSYVFVPYDtLLYSLPYKHEPYAVLRN-NSKLRRAYDAVLTITMESPEGS 266

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402624253  91 EFEKF-----SMEVKSSVEKQglnmedYVNMFVEGFHDAILLYVLALHEVLRAGySKKDGGKIIQQTWNRTFEGIAGQVS 165
Cdd:cd06371   267 FYEAFrraqeRGELPSDLDPE------QVSPLFGTIYNSIYLLAGAVENARAAG-GGVSGASLARHARNAQFPGFNQLLR 339

                         170
                  ....*....|....*...
gi 1402624253 166 IDANGDRYGDFsVIAMTD 183
Cdd:cd06371   340 TDSGGNGQPSY-VILDTD 356

Transmembrane domain of Ephrin Receptor A1 Protein Tyrosine Kinase; Ephrin receptors (EphRs) comprise the largest subfamily of receptor PTKs, and are classified into two classes (EphA and EphB), corresponding to binding preferences for either GPI-anchored ephrin-A ligands or transmembrane ephrin-B ligands. Vertebrates have ten EphA and six EphB receptors, which display promiscuous ligand interactions within each class. EphA1 has been associated with late-onset Alzheimer's disease and certain cancers such as colorectal and gastric carcinomas. EphRs contain an ephrin binding domain and two fibronectin repeats extracellularly, a single-span transmembrane (TM) domain, and a cytoplasmic tyr kinase domain. Binding of the ephrin ligand to EphR requires cell-cell contact since both are anchored to the plasma membrane. This allows ephrin/EphR dimers to form, leading to the activation of the intracellular tyr kinase domain. The resulting downstream signals occur bidirectionally in both EphR-expressing cells (forward signaling) and ephrin-expressing cells (reverse signaling). The main effect of ephrin/EphR interaction is cell-cell repulsion or adhesion. Ephrin/EphR signaling is important in neural development and plasticity, cell morphogenesis and proliferation, cell-fate determination, embryonic development, tissue patterning, and angiogenesis. The TM domain mediates dimerization.

                          10        20        30
                  ....*....|....*....|....*....|..
gi 1402624253 236 SGGLEESAVTGIVVGALLGAGLLMAFYFFRKK 267
Cdd:cd12841     5 SRGLTGGEIVAIIFGLLLGVALLLGILVFRSR 36