User:Lois A. Fridmann/Sandbox 3
From Proteopedia
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| - | ==Background and History | + | ==Background and History== |
| - | + | Tumor susceptibility gene 101, also known as Tsg101, is a human gene that encodes for a cellular protein of the same name. | |
| + | Tsg101 generally assists in sorting ubiquinated proteins into the late endosomal compartments. It does this by acting as a subunit to the ESCRT-1 protein (Endosomal Sorting Complex Required for Transport), thus forming a complex. The complex then sorts in multivescular bodies (MVB) and transports proteins marked to the lysosome for degredation. | ||
| - | + | Normally the tetrapedpide PSAP binding motif on the endosomal protien Hrs (----) binds to the Tsg101 during this sorting and trafficking process. | |
| - | Group-specific antigen | + | The Human Immunodefiency Virus (HIV) is the causative agent of acquired immunodefiency syndrom (AIDS) in which the immune system of a human begins to fail, leading to life threatening infections. Tsg101 plays an important role in the pathogenesis of HIV. In the event that the retrovirus is present in the host cell, the Gag p6 motif on HIV mimics the Hrs and binds to the P(S/T)AP binding pocket to gain access to the downstream machinery and initiate budding. The Gag is a Group-specific antigen and contains the genetic material that codes for the core structural proteins of retroviruses. |
| - | + | It acts as a negative growth regulator involved in the budding of many viruses. The UEV domain is required for the interaction of the complex with ubiquitin. It also mediates the interaction with PTAP/PSAP motifs of HIV-1 p6 protein and human spumaretrovirus Gag protein. | |
| - | + | Ubiquitination inactivates Tsg101, possibly by regulating its shuttling between an active membrane-bound protein and an inactive soluble form. Tsg101 belongs to the ubiquitin-conjugating enzyme family. UEV subfamily. | |
Revision as of 20:40, 30 April 2009
Tsg101 UEV Domain with a HIV-1 PTAP binding pocket - Residue Mutations in the C-Terminal End
Contents |
Background and History
Tumor susceptibility gene 101, also known as Tsg101, is a human gene that encodes for a cellular protein of the same name. Tsg101 generally assists in sorting ubiquinated proteins into the late endosomal compartments. It does this by acting as a subunit to the ESCRT-1 protein (Endosomal Sorting Complex Required for Transport), thus forming a complex. The complex then sorts in multivescular bodies (MVB) and transports proteins marked to the lysosome for degredation.
Normally the tetrapedpide PSAP binding motif on the endosomal protien Hrs (----) binds to the Tsg101 during this sorting and trafficking process.
The Human Immunodefiency Virus (HIV) is the causative agent of acquired immunodefiency syndrom (AIDS) in which the immune system of a human begins to fail, leading to life threatening infections. Tsg101 plays an important role in the pathogenesis of HIV. In the event that the retrovirus is present in the host cell, the Gag p6 motif on HIV mimics the Hrs and binds to the P(S/T)AP binding pocket to gain access to the downstream machinery and initiate budding. The Gag is a Group-specific antigen and contains the genetic material that codes for the core structural proteins of retroviruses.
It acts as a negative growth regulator involved in the budding of many viruses. The UEV domain is required for the interaction of the complex with ubiquitin. It also mediates the interaction with PTAP/PSAP motifs of HIV-1 p6 protein and human spumaretrovirus Gag protein.
Ubiquitination inactivates Tsg101, possibly by regulating its shuttling between an active membrane-bound protein and an inactive soluble form. Tsg101 belongs to the ubiquitin-conjugating enzyme family. UEV subfamily.
(Generalized to other viruses: A large number of viruses in other families conserve the PTAP binding site, conserving something that is affective for other viruses)
Structural and Chemical Details of C-terminal mutant Tsg101
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| 1m4p, 20 NMR models () | |||||||||
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| Gene: | tumor susceptibility gene 101 (Homo sapiens), Gag (Human immunodeficiency virus 1) | ||||||||
| Related: | 1kpp, 1kpq, 1m4q | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
The specific HIV Tsg101 Ubiquitin E2 Variant (UEV) domain model represents the wild type version of the Tsg101 UEV domain with specific highlights of the PTAP binding site featured as a green backbone, three residues in the PTAP binding site (, , ), which are also colored green, four C-terminal domain residues , , colored orange and colored yellow, and two residues included in the Ubiquitin binding site featured as a cyan colored backbone (, ).
The three residues featured in the PTAP binding pocket exhibit potential areas where mutations can occur that results in the elimination or reduction of the HIV-1 Gag protein binding. The two residues featured in the Ubiquitin binding pocket feature potential areas where mutations can occur that inhibits Ubiquitination of the Tsg101 or the p6 region of the Gag binding to the PTAP binding pocket. However, the main focus of the model is the C-terminal region of the UEV domain where the mutation of certain amino acid residues, which are not directly involved in the PTAP binding pocket result in the elimination or reduction of binding to the Gag protein. A mutation of W117 (yellow residues), which is conserved in all E2 enzymes, to A117 eliminates binding entirely. Mutations of Y110, Y113 and K118 (orange residues), which are unique to the Tsg101, to W110, V113 and A118 reduce binding by 31%, 33% and 50% respectively.
Additional Mutations
Contributions to Future Research and Therapies
Identification of mutations of various residues within and surrounding the PTAP binding site that inhibit HIV-1 Gag binding can help provide important information and avenues for future research on viral treatment and vaccination.
References
1. Pornillos O, Alam S, Davis D, Sundquist W. 2002. Structure of the Tsg101 UEV domain in complex with the PTAP motif of the HIV-1 p6 protein. Nature Structural Biology 9:812 – 817.
2. Tavassoli A, Lu Q, Gam J, Pan H, Benkovic S, Cohen S. 2008. Inhibition of HIV Budding by a Genetically Selected Cyclic Peptide Targeting the Gag-TSG101 Interaction. American Chemical Society, Chemical Biology 3:757 - 764.
3. VerPlank L, Bouamr F, LaGrassa T, Agresta B, Kikonyogo A, Leis J, Carter C. 2001. Tsg101, a homolgue of ubiquitin-conjugating (E2) enzymes, binds the L domain of HIV type 1 Pr55Gag. Proceeding of the National Academy of Science 98:7724 – 7729.
4.
