Sandbox Reserved 200: Difference between revisions
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==Trimers== | ==Trimers== | ||
RNase A trimers are formed in the same way as the dimers, except there are now three monomeric subunits. There is both a major and minor trimer. The structure of the major trimer is not known, but the two trimers can be separated by both chromatography and gel electrophoresis. <ref name="liu01"/> The major trimer is more common than the minor trimer. | |||
<Structure load='1JS0' size='400' frame='true' align='left' caption='Minor Trimer of RNase A' scene='Sandbox_Reserved_200/Minor_trimer/1' /> | <Structure load='1JS0' size='400' frame='true' align='left' caption='Minor Trimer of RNase A' scene='Sandbox_Reserved_200/Minor_trimer/1' /> | ||
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| This Sandbox is Reserved from Feb 02, 2011, through Jul 31, 2011 for use by the Biochemistry II class at the Butler University at Indianapolis, IN USA taught by R. Jeremy Johnson. This reservation includes Sandbox Reserved 191 through Sandbox Reserved 200. |
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Oligomers of Bovine Ribonuclease AOligomers of Bovine Ribonuclease A
IntroductionIntroduction
Bovine pancreatic ribonuclease A (RNase A) is an enzyme that catalyzes the hydrolysis of RNA through acid-base catalysis. RNase A has the capability to structurally form dimers, trimers, tetrmers, and pentamers based on the structure of the RNase A monomer. Though there are many oligomers, the stucture is only known for the major dimer, minor dimer, and minor trimer. Unlike the monomers, all the oligomers are capable of catalyzing the hydrolysis of double stranded RNA (dsRNA).[1] The oligomers are formed by 3D domain swapping, which can occur once or twice per monomeric unit [2]. The 3D domain swapping has no impact on the formation of active sites which is the same in the monomers and all oligomers.[2] The oligomers of RNase A also show medical relevance when looking at antitumor drugs as well as the possible cause of Alzheimer's.
DimersDimers
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Ribonuclease A has both a and dimer which are very similar to one another. Though they are similar, they are formed by different types of 3D domain swapping. 3D domain swapping occurs when identical domains are interchanged. The major dimer is formed by 3D domain swapping the β-strand of the C-terminus.[3] The minor dimer, on the other hand, is formed by 3D domain swapping of its α-helix of the N-terminus [3]. Domain swapping is extremely specific and can only occur at the or the .
Both dimers conserve the structure of the two monomers except for the conformation at the hinge loops. The
is the location where the two monomers connect acting like the hinge of a door.[2] The most important component of the hinge loops is Ala19. gives these hinges their flexibility. This flexibility allows the dimers to adopt different orientations.[3]
Not only is the structure of the monomers conserved in the dimers, but the active is also conserved. [3] The active site of both dimers contains His12, Lys41, and His119 residues. The active sites are a composite of the monomer subunits containing His12 from one monomer and His119 form the other monomer.[2] During domain swapping, the active site is not disturbed, so the dimers are able to retain their enzymatic activity. In fact, the enzymatic activity of RNase oligomers is higher than that of the monomers.[4]
TrimersTrimers
RNase A trimers are formed in the same way as the dimers, except there are now three monomeric subunits. There is both a major and minor trimer. The structure of the major trimer is not known, but the two trimers can be separated by both chromatography and gel electrophoresis. [4] The major trimer is more common than the minor trimer.
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The
Medical RelevanceMedical Relevance
Alzheimer’s disease is a terminal disease that slowly degenerates the brain. One of the possible causes of Alzheimer’s is amyloid deposits throughout the brain. Though RNasa A oligomers are not the amyloid deposits that cause Alzheimer’s, the folding of these oligomers gives clues towards the formation of amyloid deposits responsible for Alzheimer’s.
The 3D domain swapping has many similarities with the formation of amyloid fibers. Both are highly specific reactions coming from only one type of monomer and these reactions can form linear aggregates. [4] These aggregates of proteins are formed by hydrogen bonding at the hinge loops which form an antiparalell β-pleated sheet. [4] This most commonly happens with the major dimer. Liu suggests that all proteins are capable of forming aggregates by domain swapping as long as they are in high concentration and partially destabilized. [4] As 3D domain swapping becomes more understood, it will offer insight to the amyloid formation in Alzheimer’s patients.
The RNase A 3D domain swapped oligomers show significant biological activity including allostery, antitumor, and immunorepression activity. In antitumor activity, the oligomers degrade dsRNA, but they are also capable of degrading DNA and RNA hybrids which can be found during the translation of genes.[1] This same activity has not been observed in the monomer and the non-3D domain swapped oligomers .[3] This could be due to the fact that the monomer has a cystolic RNase A inhibitor that is unable to inhibit the active sites of the oligomers. [4]
All oligomers of RNase A have antitumor activity, but the higher ordered oligomers show greater activity. [1] Though the higher ordered oligomers are more active, they are also much more unstable when in vivo. The pathway of the oligomer once it is inside the cell is unknown, but the activity seems to be unregulated. [1] In cancer cells the movement of proteins through nuclear pores is unregulated, therefore oligomers can sometimes enter into the nucleus. Once the oligomer is in the nucleus, it is able to degrade RNA and DNA hybrids.[1] This will eventually prevent the cell from dividing and decrease the tumor size. Before oligomers can be used as an antitumor drug, the pathway of high ordered oligomers into the cell needs to be monitored, as well as their function within the cell. This needs to occur to prevent the degradation of dsRNA in healthy cells.
Literature CitedLiterature Cited
- ↑ 1.0 1.1 1.2 1.3 1.4 Matousek J, Gotte G, Pouckova P, Soucek J, Slavik T, Vottariello F, Libonati M. Antitumor activity and other biological actions of oligomers of ribonuclease A. J Biol Chem. 2003 Jun 27;278(26):23817-22. Epub 2003 Apr 14. PMID:12697760 doi:10.1074/jbc.M302711200
- ↑ 2.0 2.1 2.2 2.3 Liu Y, Gotte G, Libonati M, Eisenberg D. A domain-swapped RNase A dimer with implications for amyloid formation. Nat Struct Biol. 2001 Mar;8(3):211-4. PMID:11224563 doi:10.1038/84941
- ↑ 3.0 3.1 3.2 3.3 3.4 Clemo FA. Urinary enzyme evaluation of nephrotoxicity in the dog. Toxicol Pathol. 1998 Jan-Feb;26(1):29-32. PMID:9502384
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Liu Y, Gotte G, Libonati M, Eisenberg D. Structures of the two 3D domain-swapped RNase A trimers. Protein Sci. 2002 Feb;11(2):371-80. PMID:11790847