C-terminal transmembrane domains

Synaptobrevin 2 is a small protein composed of 118 amino acids. It contains a SNARE motif with a short N-terminal proline-rich extension but lacks an independently folded N-terminal domain. Like syntaxin 1, the protein possesses a C-terminal transmembrane domain that is connected to the SNARE motif by a short linker (Figure 1). Synaptobrevin is palmitoylated at cysteine residues close to its transmembrane domain. Synaptobrevin 2 is highly expressed in neurons and neuroendocrine cells, but unlike syntaxin 1 it is also present in many non-neuronal tissues albeit at low levels. 

The C-terminal transmembrane domain of /i-secretase is not strictly required for activity, but location of enzyme and substrate in the same membrane enhances kinetics and specificity. 

A second member of the ceruloplasmin family multicopper oxidases with six BCB domains was recently identified as the causative agent of sex-linked anemia (sla) in mice (Vulpe et al., 1993). It was named hephaes-tin and shown to be expressed mostly in the small intestine and the colon, where it is presumably involved in gastrointestinal iron uptake. Hephaes-tin displays a high level of sequence identity to ceruloplasmin and differs from it only by an additional C-terminal transmembrane domain, which anchors the protein to the cell membrane. A 582-nucleotide in-frame deletion in the mRNA for hephaestin sla mice has been identified compared to normal animals. The mice with such a mutation are unable to release iron from enterocytes (intestinal epithelial cells) into the circulation, which results in severe anemia. The GPI-anchored form of ceruloplasmin could potentially also mediate similar cellular iron efflux in the central nervous system. There is a transferrin-independent iron uptake system that requires Fe(III) to be reduced to Fe(II) at the cell surface for uptake to occur (DeSilva et al., 1996). Ceruloplasmin would oxidize Fe and prevent its uptake by this mechanism. Briefly, the role of ceruloplasmin is most likely to prevent excessive intracellular iron accumulation by tightly controlling iron efflux and inhibiting its uptake. 

The plant alkaloid ryanodine selectively binds with low nanomolar affinity to the ion-conducting conformational state of the ryanodine receptor. This property makes it a useful pharmacological probe to study the regulation of channel activation. The ryanodine binding site has been localized in the pore region of the C- terminal transmembrane domain (6 7). 

Fig. 8. (a) Structure of the full-length Rieske protein from bovine heart mitochondrial bci complex. The catalytic domain is connected to the transmembrane helix by a flexible linker, (b) Superposition of the three positional states of the catalytic domain of the Rieske protein observed in different crystal forms. The ci state is shown in white, the intermediate state in gray, and the b state in black. Cytochrome b consists of eight transmembrane helices and contains two heme centers, heme and Sh-Cytochrome c i has a water-soluble catalytic domain containing heme c i and is anchored by a C-terminal transmembrane helix. The heme groups are shown as wireframes, the iron atoms as well as the Rieske cluster in the three states as space-filling representations. 

The definition of the primary structure of synaptotagmin-1, composed of an N-terminal transmembrane region and two C-terminal C2-domains (Figure 3), led... 

The TJPs form an intricate complex of transmembrane (occludin, claudins, junctional adhesion molecule-1) and cytoplasmic (zona occludens-1 and -2, cingulin, AF-6, and 7H6) proteins linked to the cytoskeleton (Hawkins and Davis, 2005) (Fig. 1). Occludin was the first TJP discovered. It is a 60- to 65-kDa protein with four transmembrane domains and two extracellular loops that span the cleft between adjacent endothelial cells (Furuse et al., 1993 Hirase et al., 1997 Hawkins and Davis, 2005). Occludin is highly expressed in cerebral endothelium (Fig. 2) and sparsely distributed in nonneural endothelia (Hirase et al., 1997). The phosphorylation state of occludin regulates its association with the cell membrane (Hirase et al., 2001). In experimental autoimmune encephalomyelitis, a model of multiple sclerosis, occludin dephosphorylation precedes the neurological deterioration and increased leakage of plasma proteins across the BBB (Morgan et al., 2007). The C-terminal cytoplasmic domain of occludin is involved in its association with the cytoskeleton via accessory proteins such as zona occludens ZO-1 and ZO-2 (Furuse et al, 1993). 

Epithelial cadherin (E-cadherin) has a molecular weight of 130 kDa and is found in PNS myelin. E-cadherin is a protein of the superfamily of calcium-dependent cell adhesion molecules that can usually form adherent junctions. This protein has an N-terminal extracellular domain, a short transmembrane domain and a C-terminal intracellular domain. 

MHC Class II proteins are more restricted and are found only on the surface of certain cell types, such as B lymphocytes, some T lymphocytes and some macrophages and macrophage-like cells. They have a 33 kDa a-chain and a 28 kDa )S-chain. Both a- and /3-subunits have N-terminal extracellular, transmembrane and C-terminal intracellular domains. 

The last motif, HCHXYZH, resides 60-90 residues carboxyl-terminal to the third one and, except in the case of those MCOs that are type 1 membrane proteins (with a carboxyl-terminal transmembrane domain), is found within 30-50 residues of the C-terminus. Although there is no pattern to the XYZ in this motif, two features are conserved to either side of it. First, the three residues immediately amino-terminal to the HCH element are typically nonpolar with W as a highly conserved - 3 residue. Second, the residue in the -I- 5 position relative to the carboxyl-terminal H is either M or L/F in >90% of MCO sequences. The significance of this second conserved feature is that the sulfide -S- of an M at this position occupies a fourth coordination site in the distorted tetrahedral ligand field (alternatively described as trigonal pyramidal) of the type 1 Cu(II) in those proteins with that sequence. In some cases, the limited S Cu CT from this thioether group appears to modulate the redox potential of the coordinated Cu(II).3 -i ... 

Class lib HDACs (6 and 10) are also characterized by homology to yeast HDA1, but possess two deacetylase-like domains. However, only in HDAC6 are both functional. The C-terminal catalytic domain of HDAC 10 is only partially present and does not retain activity [23, 24]. HDAC6 is ubiquitously expressed and cytoplasmic in location. It is promiscuous in its substrates which include chaperones, transmembrane proteins, a-tubulin, and cortactin [25-27]. HDAC10 has been identified as multiple splice variants. It is broadly expressed across cell types and has both a nuclear and cytosolic intracellular distribution. The C-terminal region contains putative retinoblastoma protein-binding domains [5]. 

Another important difference between the presendy perfomed in vitro experiments in solution and the situation in vivo is that PrP is most likely formed at the surface of membranes, either within caveolae-like domains (Kaneko et al, 1997) or in endosomes (Borchelt et al, 1992 Arnold et al, 1995), whereas the recombinant proteins lack a C-terminal transmembrane anchor. It is also striking that among the numerous amyloid diseases in humans including Alzheimer s disease,... 

NDST can be divided into two domains the N-terminal deacetylase domain (within 600 amino acid residues of the N-terminus) and the C-terminal sulfotransferase domain (including about 280 amino acid residues). Both domains have been expressed and proved to contain the anticipated activities." " In addition, NDST is a typical type II membrane-bound protein with the transmembrane domain at the N-terminus. 

The structures of three cytokine receptor C2HRs and tissue factor (TF) have been determined (see Table I and Chill et al., 2003 Harlos et al, 1994 Josephson et al, 2001 Randal and Kossiakoff, 2001 Thiel et oL, 2000 Walter et al, 1995). The general features of the C2HR are shown in Fig. 8. It consists of two /3-sandwich domains, D1 and D2, connected by a short linker containing 1 turn of a- or 820 helix. The cytokine binding site is comprised predominantly of the loops located at the D1 and D2 interface. The N-terminal D1 domain is most distal from the cell membrane, while the C-terminal D2 domain is followed by a short tether of 5-12 amino acids in length before the beginning of the transmembrane helix. 

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