Membrane-embedded helices

Further considerations here do not depend critically on the accuracy of the working model of Fig. 2. Indeed, the interdomain cleft may as well be at the side of the molecule near the surface of the membrane as can be imagined from inspection of the structures proposed by Taylor et al. [75] and Stokes and Green [76] for the Ca -ATPase. It is only important to stipulate that the molecule contains at least two domains and a cluster of membrane-embedded helices. 

No direct three-dimensional structure determination of any GPCR bus been carried out yet However, die structure of the membrane-embedded helices of bucteriorhodopsin has been solved by electron crystallography [131]. Experimental data from deletion mutations, antibody targeting, and proteolytic digestion experiments provide evidence (hat the overall features of GPCRs and... 

Role of Membrane-Embedded Helices 1 and 2 in Electrogenic H+ Transport... 

The reaction centers are embedded in the cytoplasmic membranes of the bacteria, with the bottom of the structure, as shown in Fig. 23-31, protruding into the cytoplasm and the heme protein at the top projecting out into the periplasm which lies within infoldings of the plasma membrane. Subunits L and M each contain five 4.0 nm long roughly parallel helices, which span the cytoplasmic membrane. Another membrane-spanning helix is contributed by subunit H, which is located mainly on the cytoplasmic side. An approximate twofold axis of symmetry relates subunits L and M and the molecules of bound chlorophyll and pheo-phytin. 

The rhodopsin structure places the il loop adjacent to the short eighth membrane-embedded a-helix. With the exception of the 5-HT4A receptor (six residues), the 5-HT receptors have the same length as the rhodopsin loop (seven residues). Interestingly a XKKLXXX motif is conserved between the rhodopsin sequence and the majority of the 5-HT sequences, suggesting that the il loops of rhodopsin and the 5-HT receptors could have a common structure. Systematic mutagenesis studies have not been conducted. 

A membrane-embedded hairpin structure for the c subunit was established from genetic studies.31 The role of cAsp-61 in the second membrane helix of the c subunit has been studied in detail the cAsp-61— Asn or Gly mutants showed no proton conduction or ATP synthesis.99 Binding of DCCD to this residue blocked proton conduction. These results are consistent with the notion that cAsp-61 is part of the proton pathway. The carboxyl residue at position 61 was able to be transferred to the corresponding position of the first helix.100 Vacuolar-type ATPase has a similar proteolipid subunit possibly evolved from the same ancestral protein as the c subunit.25 The vacuolar proteolipid has glutamate in the middle of the fourth membrane-spanning helix, corresponding to the position of c Asp-61 of the c subunit. The glutamate may play an important role in proton conduction similar to the c subunit.101 ... 

The SPLIT algorithm was optimized for predicting transmembrane a-helices by using the Kyte-Doolittle hydropathy scale to create profile of a-helix preferences. The digital version of prediction for transmembrane a-helices is designated as the TMH predictor. Predicted profile of P-strand preferences can be used to find sequence location of potential membrane-embedded or surface-attached P-strands. The score for potential membrane-attached P-strand... 

One letter amino acid codes are used in the second column (AA). Predicted structure (PS) in the third column can be a-helix (H), P-sheet (B) or coil (C) structure that includes turn and undefined structure. Residues predicted in the transmembrane helix configuration (PTM) in the fourth column are labeled with letter NT except for highly probable TMH conformation when letter O is used. Residues with a potential to form transmembrane P-strands are labeled with letter E in the fourth column. The coil (C) conformation from third column is specified as undefined (U) or turn (T) conformation in the fourth column. Fifth to eighth column contain smoothed preferences for a-helix (PH), P-sheet (PB), turn (PT) and undefined (PU) conformation. The columns 9 and 10 contain numerical values for hydrophobic moments calculated in the case of assumed a-helix configuration (MA) and for moments calculated for assumed P-sheet configuration (MB). Last two columns contain PH-PT difference of preferences (H-T) that helps in visual identification of predicted transmembrane helices and PB+MB-2.0 scores that help in prediction of potential membrane-embedded P-strands. 

Integral membrane proteins. Membrane proteins are hard to crystallize178 and precise structures are known for only a few of them.179-181 A large fraction of all of the integral membrane proteins contain one or more membrane-spanning helices with loops of peptide chain between them. Folded domains in the cytoplasm or on the external membrane surface may also be present. The best-known structure of a transmembrane protein is that of the 248-residue bacteriorhodopsin. It consists of seven helical segments that span the plasma membrane (Fig. 23-45) and serves as a light-activated proton pump. Other proteins with similar structures act as hormone receptors in eukaryotic membranes. A seven-helix protein embedded in a membrane is depicted in Fig. 8-5 and also, in more detail, in Fig. 11-6. 

Cytokines all function using a group of transmembrane receptors embedded in the plasma membranes of target cells. The receptors have no tyrosine kinase activity but associate with and activate kinases known as Janus kinases (JAKs). These kinases phosphory-late tyrosine side chains in their receptors, and the phosphorylated receptors activate transcription factors of the STAT (signal transducer-activators of transcription) group.186-195 The specificity of cytokine action results from a combination of receptor recognition and recognition of the various STAT molecules by different JAKs.111 Cytokines have a variety of structures. Many are helix bundles or have (3 sheet structures (Fig. 30-6). 

The a helix is an important component of integral membrane proteins. These are proteins that traverse the hydrophobic plasma and organelle membranes (see Chapter 9) and perform important biologic functions. The portion of the protein that is embedded in the membrane is a-helical because the a helix provides for a maximum number of hydrogen bonds, which serve to reduce the hydrophilic nature of peptide linkages. The side chains of such trans-membrane a helices are also hydrophobic, even though under normal circumstances, such amino acids would prefer to form other secondary structures. 

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