Structural Biochemistry/Lipids/Lipid Rafts

Overview

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Researchers have learned much of what they know about membranes by constructing artificial membranes in the laboratory. In artificial membranes, different lipids separate from each other based on their physical properties, forming small islands called lipid rafts. Thus, Lipid rafts are possible island like structure present in cellular membranes.

These rafts have a higher concentration of certain specialized lipids, called glycosphingolipids, and cholesterol than do non-raft parts of the membrane. Rafts also are distinguished by a different assortment of proteins. Certain types of proteins cluster together in rafts, while others remain mostly outside of rafts. The big question is, to what extent do these rafts, seen readily in artificial membranes, actually exist in living cells? Using advanced laboratory methods and imaging techniques, some researchers found evidence that rafts, indeed, do form in living cellular membranes, but these rafts may be small and transitory. Although the existence of lipid rafts in cellular membranes remains controversial, many scientists believe they serve as communication hubs by recruiting proteins that need to come together in order to transmit a signal. Researchers are beginning to link lipid rafts with a variety of diseases, including AIDS, Alzheimer’s, anthrax, and atherosclerosis.

File:Membrane raft.gif

Lipid Raft Structure

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Structural Details

The amount and types of proteins and lipids found in membranes can vary depending on the membrane's location in the body or which organelle it surrounds. These differences allow a wide variety of processes to be performed with membranes. In the fluid mosaic model, lipids and proteins exhibit lateral mobility and are constantly changing positions. Cholesterol and sphingolipids, which include both sphingomyelin and glycosphingolipids, are also commonly found in membranes. It has been assumed that individual proteins and lipids move independently and randomly, but some patches of aggregation have been observed in membranes, too. Relatively new studies using artificial membranes have shown that certain proteins and lipid patches tend to aggregate with each other to form island-like LIPID RAFTS. These island-like lipid rafts can be analogous to Jello with embedded fruits where the fruits play the role as proteins. Lipid rafts have a noticeably higher concentration of cholesterol and glycosphingolipids than other areas of the membrane. Certain types of proteins are also more likely to be found in rafts than others. Specifically, an example of a protein found in lipid rafts are acylated proteins, and some have proposed that the reaction between cholesterol and their unsaturated acyl chains promotes the formation of lipid rafts. Also, proteins have been associated with lipid rafts via glycosylphosphatidylinositol (GPI) anchors, which covalently attach proteins at the membrane's external service. There is still question as to the existence of lipid rafts in living cells, so the current theory is that the lipid rafts likely do exist but are small and transitory.

Sphingolipids

Examples of common sphingolipids include sphingosine and sphingosine 1-phosphate. They are crucial in regulating many cellular processes—such as migration, proliferation, differentiation, and immune responses. These sphingolipids are central for cellular signaling, more knowingly familiar as a bioactive lipid mediator.

Recent evidences have proven that the signaling function of these sphingolipids indicate association of apoptosis and growth arrest. Sphingosine is capable of directly inhibiting protein kinase C, along with other effects on various protein kinases in vitro. Additionally, sphingosines have shown signs of regulating the pro-survival adaptor protein 14-3-3 by directly interacting with it and enabling the phosphorylation and inactivation of the adaptor component via protein kinases. Examples of this are shown in PKA and PKC-gamma. By doing so, the pro-survival pathway is completely barricaded.

Another common sphingolipid is ceramide, which like sphingosine, is associated with apoptosis. Ceramide correlated with growth arrest and apoptosis through levels of various responses of stress stimuli. Ceramide demonstrates modulation of proteins either through direct catalytic activities, or by facilitation of subcellular localization.

As a result, regulation of sphingosine kinase activity has illustrated crucial cellular functionality. Monitoring of such kinases allowed the determination of cell fate, whether a cell will survive or proliferate. Additionally, studies of sphingosine kinases have assisted in the control of adhesion, differentiation, and immune reaction and have increased possibilities of providing powerful information for therapeutic actions.

Types and Functions of Lipid Rafts

Two types of lipid rafts have been proposed: planar lipid rafts, also called glycolipid rafts, and caveolae. Planar rafts are continuous with the plane of the plasma membrane and do not have distinctive morphological features. Caveolae, on the other hand, are flask shaped inward foldings of the plasma membrane that contain caveolin proteins, which are a group of proteins involved in receptor-independent endocytosis.

It has been proposed that lipid rafts serve to collect proteins when needed for signal transmissions and are possibly linked to diseases like AIDS. The ability to recruit signaling proteins and molecules into their island-like microdomains would give lipid rafts the possibility to play an important role in neurotransmitter signaling. The hypothesis for this is that the environment of lipid rafts promote kinetically favorable interactions required for signal transduction. On the other hand, they could also potentially serve to separate signaling molecules and decrease signals by inhibiting the interactions. The caveolin types of lipid rafts could possibly be involved with endocytosis and cholesterol transportation, too.

Controversy about Lipid Rafts

One of the primary reasons for the controversy over lipid rafts has stemmed from the challenges of studying lipid rafts in living cells. Lipid rafts are small microdomains ranging from 10–200 nm in size, which is below the classical diffraction limit of a light microscope. This means lipid rafts are quite difficult to visualize, let alone observe in action. Also, experimental studies of lipid rafts have led many to believe that they are transitory and do not remain intact for very long. An argument against the useful existence of lipid rafts in living cells is that the time scale of their actual existence is unknown. If lipid rafts exist, they may only occur on a rapid time scale that is too short to serve much purpose and therefore irrelevant to biological processes.

References

1. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=&_xRefDocId=pii%23b012443710900363x&_user=4429&_fmt=high&_orig=na&_cdi=20141&_refWorkId=264&view=c&_acct=C000059602&_version=1&_urlVersion=0&_userid=4429&md5=22bb48e7aeabf3a57722193092abfd22, Science Direct, Encyclopedia of Biological Chemistry, Pg. 584-587, 12/2/2009

2. Inside the Cell, U.S. Department of Health and Human Services, 12/2/2009

3. http://www.uoguelph.ca/~fsharom/research/gpi.html

4. http://www.bms.ed.ac.uk/research/others/smaciver/Cyto-Topics/lipid_rafts_and_the_cytoskeleton.htm