Paper

Kyle Cubin
2-12-06
Paper #1
Membrane Attack Complex


Membrane Attack Complex: The Oil Drill Molecular Machine


A human’s immune system has the ability to protect the body from nearly all dangers detrimental to its health. The complement system is one of the most crucial mechanisms of the immune system because of its ability to drill through the membrane of an antigen, or infected cell, and effectively destroy it. The system has various pathways and processes, but in the end it all leads to one destructive machine, the membrane attack complex which effectively drills through the cell’s membrane and induces cell lysis. The membrane attack complex is a combination of five different proteins that come together to form the final mechanism for killing the antigen, each protein serving a different purpose in creating a new molecule that has a new independent role. The membrane attack complex is a natural molecular machine that is a great example of the potential of bionanotechnology.
The complement system has three different pathways that all lead to the membrane attack complex. The first pathway is the Classical Pathway, which is part of the specific immune response. This means is that this pathway is very specific to what it attacks because it is looking for a unique antigen that triggers the response. The initial step for this pathway is for antibodies to recognize the foreign cell and attaching to the cells surface, allowing the C1-complex to bind to the antigens. From this point, the new C1-complex begins to cleave subsequent proteins in a cascade of events that leads to the formation of C3-convertase. Now the Alternative Pathway starts, which is also capable of beginning in the innate immune response without the proceeding Classical Pathway. So in this pathway the initial protein does not need the antigen to be recognized by antibodies to bind to the surface. The starting point of this process is C3 hydrolosis, which breaks the C3 protein into C3a and C3b. C3b then cleaves C5 into C5a and C5b, and C5b then becomes the starting point of the membrane attack complex (MAC). The third pathway, or the Lectin Pathway, is essentially the classical pathway, but instead of utilizing the C1-complex it uses opsonin, mannan-binding lectin (MBL) and ficolins. The pathway also utilizes different serine proteases than the other pathways do.
The pathways involved in the complement system serve two main purposes. The first is to put protein segments into the bloodstream to draw more lymphocytes, or white blood cells, to the site of infection. The second purpose is to form the membrane attack complex. The membrane attack complex will basically drill a hole in the antigen cell, which allows free diffusion of molecules in and out of the cell, leading to the death of the cell. The membrane attack complex is formed by five different kinds of proteins; C5b, C6, C7, C8, and C9. The structure of these proteins is crucial to the formation of the MAC. C5b possesses a metastable binding site, most likely caused by the expression of a hydrophobic site that is specific to C6. C6 and C7 have very similar molecular structures; they are both single-chained glycoproteins and considered to be serine proteases. C8 is made up of three non-identical chains; the alpha and gamma chains are disulfide linked and the beta chain is covalently associated with the alpha-gamma complex. C9 has a structure such that if cleaved a hydrophilic segment, C9a, and a hydrophobic segment, C9b, is produced. C9a represents the NH2-terminal end of the molecule and the C9b is the NOOH-terminal segment. It is thought that the hydrophilic nature of C9a is important for binding to the C5b-8 complex, while the hydrophobic C9b site is important for anchoring the MAC into the cell membrane.
The actual process of the formation of the MAC is a cascade of steps each having to occur in a given order. The process begins with the C5 protein being cleaved into C5a and C5b, C5a is released into the blood as a chemokine to attract neutrophils, a type of innate white blood cells, to the site of infection. Alternatively, the C5b segment attaches to the cell surface which exposes the metastable binding site for the C6 protein. After the C6 protein has bound to the C5b protein, the C7 protein can come and attach to the C5b-6 complex forming the C5b-7 complex. This complex now expresses hydrophobic regions that are capable of inserting into the membrane, thus forming the anchoring device of the MAC. The C7 also forms a site with specificity for the C8 protein that binds to the entire complex. The new C5b-8 complex has a receptor for numerous C9 proteins and once the initial C9 protein binds the process of C9 oligomerisation starts. Essentially, C9 oligomerisation is the binding of at least twelve C9 proteins in a circular shape as each protein punches into the cell membrane. It is at this point that the MAC is finished and the cell lysis begins, leading to the ultimate death of the cell.
It is apparent that the membrane attack complex is an effective cell killer, but it has potential to damage healthy cells if left unregulated. The complement system has been proven to have direct relationships with autoimmune syndromes, including issues as severe as the destruction of vascular integrity in a lung allograft and causing secondary injuries following spinal cord trauma. There are certain proteins involved in the regulation of the MAC to prevent from autoimmune attacks; the first is the S-protein. This is the primary inhibitor of the attachment of the MAC to the cell membrane. The S-protein will actually bind to the metastable site on the C5b-7 complex that would normally bind to the lipid membrane. This prevents the complex from ever getting anchored into the cell and beginning to destroy it. The S-protein allows the rest of the formation of the MAC to be completed off the cell surface and stops short of C9 polymerization. C9 polymerization stops short because of the S-protein, which also regulates the formation of the ring of C9 proteins that will puncture the hole in the cell membrane. The next regulatory protein is on the cell surface and is called CD59. CD59 is considered to be the most effective inhibitor of the complement process. CD59 exists on human cells and will bind to the C5b-8 or C5b-9 complexes and not allow the complexes to secure themselves to the cell surface directly; therefore the hole is never punctured into the cell.
Without the membrane attack complex, the human immune system would not be nearly as effective. The complement cascade is involved in both the innate and adaptive immune response and is the ultimate killer of infected cells. The structure of the MAC is very particular and results completely from the configuration of the proteins that it is comprised of. Each protein has a specific site to bind to the next protein in the cascade and that site is only exposed once the previous event in the cascade occurs. The conformational changes of the proteins turn seemingly useless proteins, if left unaltered and alone, into one of the most effective molecular machines in the human body. The MAC is like an oil drill that drills through the infected cells membrane and allows the free flow of molecules. However, the power of the machine is also seen in autoimmune attacks on the body, and because of the power of the MAC it is very effective at killing healthy cells. This is why it is very important to have regulatory proteins that prevent the formation of the MAC in certain situations.

Works Cited
“Complement Membrane Attack Complex”. Wikipedia. http://en.wikipedia.org/wiki/Membrane_attack_complex. 4 December 2006.

“The Complement System”. http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/Complement.html#The_Classical_Pathway. 20 September 2006.

“The Membrane Attack Complex of Complement”. H J Muller-Eberhard. Annual Review of Immunology. Vol. 4. 503-528. April 1986.

“The Role of Complement in the Elimination of Microorganisms”. http://www-micro.msb.le.ac.uk/MBChB/Merralls/Merralls.html. Microbiology @ Leicester. 2004.