Receptors, membrane

7 INOSITOL LIPIDS PLAY SPECIFIC ROLES IN MEMBRANE PROTEIN ANCHORING 

Intrinsic proteins may be anchored in the membrane by several different mechanisms. Of these, the hydrophobic interaction of an amino acid sequence with the interior of the lipid bilayer is the most common. Such interactions include hydrophobic sequences at one end of the protein only as well as polypeptide chains which traverse the membrane (several times). In addition, some proteins may be attached through interactions with lipid. Thus, fatty acid acylation of the NH2-terminus or the formation of fatty acid thioesters with cysteine residues have been observed. In addition, a number of membrane proteins are believed to be covalently attached to phosphatidylinositol. 

The evidence that phosphatidylinositol has a role in protein anchoring comes from two sources (a) the release of certain membrane proteins following digestion with a phosphatidylinositol-specific phospholipase C and (b) analysis of the anchoring domain of some of these membrane proteins. Examples of proteins believed to be attached thus to membranes include alkaline phosphatase, acetylcholinesterase, 5 -nucleotidase and the variant surface glycoprotein (VSG) from Trypanosoma brucei, (The latter is responsible for the ability of this parasitic protozoan to evade the victim s immune defence system and so cause sleeping sickness.) 

At present we do not have a definite reason as to why some membrane proteins are attached through phosphatidylinositol. One possibility is that it may provide a means of selectively mobilizing these proteins. Indeed, there is some evidence that endogenous phospholipases may cause the release of VSG and alkaline phosphatase in soluble forms and other proteins such as acetylcholinesterase are also known to be released under certain physiological conditions. 

Recently, Cuatrecasas and associates claim to have achieved the partial purification and characterization of two novel mediator substances produced by insulin action. These substances appeared to be complex 

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G-Protein Coupling. The heterotrimeric guanosine triphosphate (GTP) binding proteins, known as G-proteins, are a principal family of proteins serving to couple membrane receptors of the G-protein family to ionic and biochemical processes. This topic is reviewed in References 63—67. 

In addition to binding to sialic acid residues of the carbohydrate side chains of cellular proteins that the virus exploits as receptors, hemagglutinin has a second function in the infection of host cells. Viruses, bound to the plasma membrane via their membrane receptors, are taken into the cells by endocytosis. Proton pumps in the membrane of endocytic vesicles that now contain the bound viruses cause an accumulation of protons and a consequent lowering of the pH inside the vesicles. The acidic pH (below pH 6) allows hemagglutinin to fulfill its second role, namely, to act as a membrane fusogen by inducing the fusion of the viral envelope membrane with the membrane of the endosome. This expels the viral RNA into the cytoplasm, where it can begin to replicate. 

Figure 13.1 The basic organization of a membrane receptor molecule consists of an extracellular domain, a transmembrane region, and an intracellular domain.

Many proteins found in nature are glycoproteins because they contain covalently linked oligo- and polysaccharide groups. The list of known glycoproteins includes structural proteins, enzymes, membrane receptors, transport proteins, and immunoglobulins, among others. In most cases, the precise function of the bound carbohydrate moiety is not understood. 

III. Tyr protein kinases A. Cytosolic tyrosine kinases src, fgr, abl, etc.) B. Receptor tyrosine kinases (RTKs) Plasma membrane receptors for hormones such as epidermal growth factor (EGF) or platelet-derived growth factor (PDGE) Raf (a protein kinase)... 

FIGURE 23.22 The metabolic effects of insulin. As described in Chapter 34, binding of insulin to membrane receptors stimulates the protein kinase activity of the receptor. Subsequent phosphorylation of target proteins modulates the effects indicated. 

Steroid hormones act in a different manner from most hormones we have considered. In many cases, they do not bind to plasma membrane receptors, but rather pass easily across the plasma membrane. Steroids may bind directly to receptors in the nucleus or may bind to cytosolic steroid hormone receptors, which then enter the nucleus. In the nucleus, the hormone-receptor complex binds directly to specific nucleotide sequences in DNA, increasing transcription of DNA to RNA (Chapters 31 and 34). 

Coupling, processes that cause the interaction of molecules with membrane receptors to produce an observable cellular response see Chapter 2.2. 

Gao ZG, Jacobson KA (2006) Allosterism in membrane receptors. Drug Discov Today 11 191-202... 

Protein toxins acting intracellularly are often composed of two subunits (A/B model). One subunit is catalytic (A-subunit) and the other is responsible for binding and cell entry (B-subunit). Following binding to an extracellular membrane receptor, the toxins are endocytosed. From the endosomes, the A-subunit is directly (pH dqDendent) transferred into the cytosol (e.g., diphtheria toxin and anthrax toxin) or the toxin is transported in a retrograde manner via the golgi to the ER (e.g., cholera toxin), where translocation into the cytosol occurs [1]. 

In addition to inhibiting cytokine synthesis by glucocorticoids, cytokine effects can be prevented by scavenging the cytokine either with neutralizing antibodies or soluble receptors or by blocking the respective cytokine plasma membrane receptors with blocking antibodies or receptor antagonists. 

Internalization is an agonist-induced endocytosis of membranous receptors which occurs in seconds to minutes. It involves the formation of receptor containing... 

Besides cytoplasmic protein kinases, membrane receptors can exert protein kinase activity. These so-called receptor tyrosine kinases (RTK) contain a ligandbinding extracellular domain, a transmembrane motif, and an intracellular catalytic domain with specificity for tyrosine residues. Upon ligand binding and subsequent receptor oligomerization, the tyrosine residues of the intracellular domain become phosphory-lated by the intrinsic tyrosine kinase activity of the receptor [3, 4]. The phosphotyrosine residues ftmction as docking sites for other proteins that will transmit the signal received by the RTK. 

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