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 1402625917  41 GDGSWKRGDKHDFEAKQAYSSLQTVTLLRTVKPEFEKFSMEVKSSVEKQGLNMEDYVNMFVEGFHDAILLYVLALHEVLR 120
Cdd:cd06386   243 GNGSWKRGDKHDFEAKQAYSSLQTVTLLRTVKPEFEKFSMEVKSSVQKQGLNDEDYVNMFVEGFHDAILLYALALHEVLR 322

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1402625917 121 AGYSKKDGGKIIQQTWNRTFEGIAGQVSIDANGDRYGDFSVIAMTDVEAGTQEVIGDYFGKEGRFEMRP 189
Cdd:cd06386   323 NGYSKKDGGKIIQQTWNRTFEGIAGQVSIDANGDRYGDFSVIAMTDVEAGTQEVIGDYFGKEGRFEMRP 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 1402625917  41 GDGSWKRGDKHDFEAKQAYSSLQTVTLLRTVKPEFEKFSMEVKSSVEKQGLNMEDYVNMFVEGFHDAILLYVLALHEVLR 120
Cdd:cd06386   243 GNGSWKRGDKHDFEAKQAYSSLQTVTLLRTVKPEFEKFSMEVKSSVQKQGLNDEDYVNMFVEGFHDAILLYALALHEVLR 322

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1402625917 121 AGYSKKDGGKIIQQTWNRTFEGIAGQVSIDANGDRYGDFSVIAMTDVEAGTQEVIGDYFGKEGRFEMRP 189
Cdd:cd06386   323 NGYSKKDGGKIIQQTWNRTFEGIAGQVSIDANGDRYGDFSVIAMTDVEAGTQEVIGDYFGKEGRFEMRP 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 1402625917 219 SGGLEESAVTGIVVGALLGAGLLMAFYFFRKK 250
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 1402625917  41 GDGSWKRGDKHDFEAKQAYSSLQTVTLLRTVKPEFEKFSMEVKSSVEKQGLNMEDYVNMFVEGFHDAILLYVLALHEVLR 120
Cdd:cd06386   243 GNGSWKRGDKHDFEAKQAYSSLQTVTLLRTVKPEFEKFSMEVKSSVQKQGLNDEDYVNMFVEGFHDAILLYALALHEVLR 322

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1402625917 121 AGYSKKDGGKIIQQTWNRTFEGIAGQVSIDANGDRYGDFSVIAMTDVEAGTQEVIGDYFGKEGRFEMRP 189
Cdd:cd06386   323 NGYSKKDGGKIIQQTWNRTFEGIAGQVSIDANGDRYGDFSVIAMTDVEAGTQEVIGDYFGKEGRFEMRP 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 1402625917  40 KGDGSWKRGDKHDFEAKQAYSSLQTVTLLRTVKPEFEKFSMEVKSSVEKQGLNM----EDYVNMFVEGFHDAILLYVLAL 115
Cdd:cd06352   240 NSTDGWERNDGRDEDAKQAYESLLVISLSRPSNPEYDNFSKEVKARAKEPPFYCydasEEEVSPYAAALYDAVYLYALAL 319

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1402625917 116 HEVLRAGYSKKDGGKIIQQTWNRTFEGIAGQVSIDANGDRYGDFSVIAMtDVEAGTQEVIGDYFG 180
Cdd:cd06352   320 NETLAEGGNYRNGTAIAQRMWNRTFQGITGPVTIDSNGDRDPDYALLDL-DPSTGKFVVVLTYDG 383

ligand-binding domain of type B natriuretic peptide receptor; Ligand-binding domain of type B natriuretic peptide receptor (NPR-B). NPR-B is one of three known single membrane-spanning natriuretic peptide receptors that have been identified. Natriuretic peptides are family of structurally related but genetically distinct hormones/paracrine factors that regulate blood volume, blood pressure, ventricular hypertrophy, pulmonary hypertension, fat metabolism, and long bone growth. In mammals there are three natriuretic peptides: ANP, BNP, and CNP. Like NPR-A (or GC-A), NPR-B (or GC-B) is a transmembrane guanylyl cyclase, an enzyme that catalyzes the synthesis of cGMP. NPR-B is the predominant natriuretic peptide receptor in the brain. The rank of order activation of NPR-B by natriuretic peptides is CNP>>ANP>BNP. Homozygous inactivating mutations in human NPR-B cause a form of short-limbed dwarfism known as acromesomelic dysplasia type Maroteaux.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1402625917  47 RGDKHDFEAKQAYSSLQTVTLLRTVKPEFEKFSME-VKSSVEKQGLNMEDYVNMFVEG-FHDAILLYVLALHEVLRAGYS 124
Cdd:cd06384   256 SSDIQWQDLREAFKTVLVITYKEPDNPEYQEFQRElIARAKQEFGVQLNPSLMNLIAGcFYDGVLLYAQALNETLREGGS 335

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1402625917 125 KKDGGKIIQQTWNRTFEGIAGQVSIDANGDRYGDFSVIAMTDVEAGTQEVIGDYFGKE 182
Cdd:cd06384   336 QKDGLNIVEKMQDRRFWGVTGLVSMDKNNDRDTDFNLWAMTDHESGQYEVVAHYNGAE 393

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 1402625917  43 GSWKRGDKHDFeaKQAYSSLQTVTLLRTVKPEFEKFSMEVKSSVEKQGLNMEDY--------VNMFVEGFHDAILLYVLA 114
Cdd:cd06370   253 GDYTKNDTKEA--LEAFRSVLIVTPSPPTNPEYEKFTKKVKEYNKLPPFNFPNPegiektkeVPIYAAYLYDAVMLYARA 330

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1402625917 115 LHEVLRAGYSKKDGGKIIQQTWNRTFEGIAG-QVSIDANGDRYGDFSVIAMTDVEAGT 171
Cdd:cd06370   331 LNETLAEGGDPRDGTAIISKIRNRTYESIQGfDVYIDENGDAEGNYTLLALKPNKGTN 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 1402625917  75 FEKFSMEVKSSVEKQGLNMEDYVNMFVEGFHDAILLYVLALHEVLRAGYSKKDGGKIIQQTWNR---TFEGIAGQVSIDA 151
Cdd:cd06372   275 RKQVHQKLRRAPFYSSISSEDQVSPYSAYLHDAVLLYAMGLKEMLKDGKDPRDGRALLQTLRGYnqtTFYGITGLVYLDV 354

                          90
                  ....*....|...
gi 1402625917 152 NGDRYGDFSVIAM 164
Cdd:cd06372   355 QGERHMDYSVYDL 367

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 1402625917 219 SGGLEESAVTGIVVGALLGAGLLMAFYFFRKK 250
Cdd:cd12841     5 SRGLTGGEIVAIIFGLLLGVALLLGILVFRSR 36

ligand-binding domain of the membrane guanylyl cyclase C; Ligand-binding domain of the membrane guanylyl cyclase C (GC-C or StaR). StaR is a key receptor for the STa (Escherichia coli Heat Stable enterotoxin), a potent stimulant of intestinal chloride and bicarbonate secretion that cause acute secretory diarrhea. The catalytic domain of the STa/guanylin receptor type membrane GC is highly similar to those of the natriuretic peptide receptor (NPR) type and sensory organ-specific type membrane GCs (GC-D, GC-E and GC-F). The GC-C receptor is mainly expressed in the intestine of most vertebrates, but is also found in the kidney and other organs. Moreover, GC-C is activated by guanylin and uroguanylin, endogenous peptide ligands synthesized in the intestine and kidney. Consequently, the receptor activation results in increased cGMP levels and phosphorylation of the CFTR chloride channel and secretion.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1402625917  98 NMFVEGFHDAILLYVLALHEVLRAGYSKKdGGKIIQQTWNRTFEGIAGQVSIDANGDRYGDFSVI 162
Cdd:cd06369   285 NDYAAAYLDGVLLFGHVLKKFLESNEAMQ-TMKFIHAFRNITFEGALGPVTLDSYGDRDVNLSLL 348