Membrane Anchoring and Signal Transduction

Transmission of signals over the cell membrane requires cooperation of the signaling proteins, each of which either exist as transmembrane proteins or are associated with the membrane. Extracellular signals are initially transmitted across the membrane with the aid of transmembrane proteins. In many cases the further signal transduction is tightly coupled to the membrane. This signal transduction, localized at the cytoplasmic side of the membrane, occurs with proteins whose function is tightly coupled with an association with the cell membrane. 

Often the cell accomphshes the association of signal proteins with the membrane by post-translationaUy affixed lipid anchors composed of hydrophobic residues, such as fatty acids, isoprenoids or complex glycolipids (see fig. 3.11). These lipid moieties of lipidated proteins favor membrane association by inserting themselves into the phospholipid bilayer. 

N-myristoyl o (l heteratrimeric G-proteins (a-sjbunit), see chapter S cytoplasmic tyrosine kinases, see chapter 8 N-terminus 

S-pBlmrtovI (S-Acy11 tieterotrimeric G-proteins a-sjbunit), G-protein-coupled receptors, see chapter 5 Has proteins, see chapter 8 internal, no distinct consensus sequence 

S-prenyl Geranylgeranyl Famesyl heterotrimeric G-proteins (y-sub unit) Ras proteins rhodopsin kinase See chapter 5 C-terminus 

An example of such a signal transduction can be found in the pathway leading to the production of cAMP, in which the signal is transmitted from a G-protein-coupled receptor to the cytoplasmic side of the membrane (see Chapter 5), where membrane-anchored heterotrimeric G-proteins become activated and transmit the signal 

Signaling proteins are targeted to the inner face of the cell membrane mainly by the following ways  

To achieve a stable and regulable membrane assodation of signaling proteins, a combination of these mechanisms may also be used. 

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PI is involved in membrane anchoring of proteins via GPI and the inositol moiety is a substrate for lipid kinases yielding phosphoinositides involved in cytoskeletal organization, vesicle transport and signal transduction. 

Analogously, it has been shown that NisK and NisP constitute the histidine proteinase kinase and response regulator components of the nisin signal transduction system [92,101,107]. NisK is a 447-residue, membrane-integrated protein with two potential N-terminal membrane anchors and a cytoplasmic carboxy-terminus [107]. The carboxy-terminus contains a His-238 residue for... 

Airother interesting facet of lipid anchors is that they are transient. Lipid anchors can be reversibly attached to and detached from proteins. This provides a switching device for altering the affinity of a protein for the membrane. Reversible lipid anchoring is one factor in the control of signal transduction pathways in eukaryotic cells (Chapter 34). 

Palmitoylation is, after myristoylation, the most common modification of the a-sub-rmit of the heterotrimeric G-proteins (see chapter 5). The a-subunit of G-proteins can be lipidated in a two-fold marmer, with a myristoic acid and a pahnitoic acid anchor at the N-terminus. It appears in this case that two lipid anchors are necessary to mediate a stable association of the protein with the membrane. The lipidation of cytoplasmic protein tyrosine kinase also includes both myristoylation and palmitoylation. H-Ras protein also requires, apart from C-terminal farnesylation (see below), a pahnitoyl modification in order to bind to the plasma membrane. In all mentioned examples the fatty acid anchors play an essential role in the signal transduction. 

The intracellular messengers are diffusible signal molecules and reach their target proteins mostly by diffusion. Close spatial proximity of the signal components, as achieved for transmembrane receptors and their effector proteins with the help of membrane anchoring or with specific protein-protein modules (see Chapter 5, Chapter 8), is not necessarily required for this type of signal transduction. 

The function of the Ras protein in cellular signal transduction is inseparably bound with the plasma membrane. The Ras proteins associate with the inner side of the cell membrane with the help of lipid anchors, such as famesyl residues and pahnitoyl residues (see 3.7). 

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