Sandbox Reserved 1105: Difference between revisions
No edit summary |
No edit summary |
||
| Line 28: | Line 28: | ||
Each monomer is composed of an α-helix and two four stranded β-sheets, which results in two eight-stranded β-sheets per dimer <ref name="seb">Sebastião, M. P., Lamzin, V., Saraiva, M. J., & Damas, A. M. (2001). Transthyretin stability as a key factor in amyloidogenesis: X-ray analysis at atomic resolution. Journal of Molecular Biology, 306(4), 733–744. doi:10.1006/jmbi.2000.4415 </ref>. There is a large solvent channel which passes between the two sheets in which two molecules of T4 can bind. Monomers associate via the formation of an eight-stranded anti-parallel β-sheet to which each monomer contributes four β-strands. These β-sheets are situated at the center of the tetramer and positioned back to back. Ile107 and Val122 of monomer A are in direct van der Waals contact with the phenol ring of Phe87 from monomer B. | Each monomer is composed of an α-helix and two four stranded β-sheets, which results in two eight-stranded β-sheets per dimer <ref name="seb">Sebastião, M. P., Lamzin, V., Saraiva, M. J., & Damas, A. M. (2001). Transthyretin stability as a key factor in amyloidogenesis: X-ray analysis at atomic resolution. Journal of Molecular Biology, 306(4), 733–744. doi:http://dx.doi.org/10.1006/jmbi.2000.4415 </ref>. There is a large solvent channel which passes between the two sheets in which two molecules of T4 can bind. Monomers associate via the formation of an eight-stranded anti-parallel β-sheet to which each monomer contributes four β-strands. These β-sheets are situated at the center of the tetramer and positioned back to back. Ile107 and Val122 of monomer A are in direct van der Waals contact with the phenol ring of Phe87 from monomer B. | ||
[[Image:2.png|thumb|left]] | [[Image:2.png|thumb|left]] | ||
| Line 40: | Line 40: | ||
And Phe64 is in van der Waals contact with Cys10 via Pro11 in monomer A. Each monomer contain a single cysteine (Cys10), which is usually bound to various sulfhydryls or sulfite from plasma. S-oxidation of Cys10 to cysteic acid has a stabilizing effect on the monomer. It may be derived from hydrogen bonds between the sulfonic oxygens of Cys10–SO3 – and Gly57 N, His56 NE and Arg104 NH1 <ref name= "Altland"> Altland, K., Benson, M. D., Costello, C. E., Ferlini, A., Hazenberg, B. P. C., Hund, E., … Winter, P. (2007). Genetic microheterogeneity of human transthyretin detected by IEF. ELECTROPHORESIS, 28(12), 2053–2064. doi:10.1002/elps.200600840</ref>. | And Phe64 is in van der Waals contact with Cys10 via Pro11 in monomer A. Each monomer contain a single cysteine (Cys10), which is usually bound to various sulfhydryls or sulfite from plasma. S-oxidation of Cys10 to cysteic acid has a stabilizing effect on the monomer. It may be derived from hydrogen bonds between the sulfonic oxygens of Cys10–SO3 – and Gly57 N, His56 NE and Arg104 NH1 <ref name= "Altland"> Altland, K., Benson, M. D., Costello, C. E., Ferlini, A., Hazenberg, B. P. C., Hund, E., … Winter, P. (2007). Genetic microheterogeneity of human transthyretin detected by IEF. ELECTROPHORESIS, 28(12), 2053–2064. doi: http://dx.doi.org/10.1002/elps.200600840</ref>. | ||
Monomers of TTR will be called A, B, C, D. And as we consider the TTR as a dimer of dimer, we have A and B the upper part of the protein and C and D the lower part. The contact between upper and lower dimers is made via β-sheet contacts, creating hydrogen bonds between main-chain atoms. In contrast to the monomer associations, contacts between the upper and lower parts are much less important so that the dimer assembly unit of TTR is best defined as the monomers which are joined by β-strand hydrogen bonding. Two funnel-shaped hormone binding sites are located at the dimer–dimer region. | Monomers of TTR will be called A, B, C, D. And as we consider the TTR as a dimer of dimer, we have A and B the upper part of the protein and C and D the lower part. The contact between upper and lower dimers is made via β-sheet contacts, creating hydrogen bonds between main-chain atoms. In contrast to the monomer associations, contacts between the upper and lower parts are much less important so that the dimer assembly unit of TTR is best defined as the monomers which are joined by β-strand hydrogen bonding. Two funnel-shaped hormone binding sites are located at the dimer–dimer region. | ||
| Line 48: | Line 48: | ||
=== TTR with natural ligands === | === TTR with natural ligands === | ||
The TTR – ligand interaction provides kinetic stabilization the protein. The more the affinity is high, the more the ligand stabilizes the complex. The dissociation constants with T4 and retinol-binding protein (RBP) are respectively from 1,1.10-7 to 1,5.10-7 M <ref name = "Monaco"> Monaco, H., Rizzi, M., & Coda, A. (1995). Structure of a complex of two plasma proteins: transthyretin and retinol-binding protein. Science, 268(5213), 1039–1041. doi:10.1126/science.7754382</ref>. | The TTR – ligand interaction provides kinetic stabilization the protein. The more the affinity is high, the more the ligand stabilizes the complex. The dissociation constants with T4 and retinol-binding protein (RBP) are respectively from 1,1.10-7 to 1,5.10-7 M <ref name = "Monaco"> Monaco, H., Rizzi, M., & Coda, A. (1995). Structure of a complex of two plasma proteins: transthyretin and retinol-binding protein. Science, 268(5213), 1039–1041. doi: http://dx.doi.org/10.1126/science.7754382</ref>. | ||
==== TTR-T4 complex ==== | ==== TTR-T4 complex ==== | ||
The crystal structure of this complex is orthorhombic <ref name="wo">Wojtczak, A., Cody, V., Luft, J. R., & Pangborn, W. (1996). Structures of Human Transthyretin Complexed with Thyroxine at 2.0 Å Resolution and 3’,5’-Dinitro-N-acetyl-L-thyronine at 2.2 Å Resolution. Acta Crystallographica Section D Biological Crystallography, 52(4), 758–765. | The crystal structure of this complex is orthorhombic <ref name="wo">Wojtczak, A., Cody, V., Luft, J. R., & Pangborn, W. (1996). Structures of Human Transthyretin Complexed with Thyroxine at 2.0 Å Resolution and 3’,5’-Dinitro-N-acetyl-L-thyronine at 2.2 Å Resolution. Acta Crystallographica Section D Biological Crystallography, 52(4), 758–765. doi:http://dx.doi.org/ 10.1107/s0907444996003046 </ref>. | ||
Two hormone binding sites are located at the dimer–dimer region bind T4 with negative cooperativity. Under physiological conditions, the bound between the natural ligand and the tetramer can’t be broken down. Moreover, there is only one hormone bound per tetramer. The negative cooperativity mechanism explain the fact that the affinity constants (Ka) for the binding of the first and the second T4 changes, they are respectively 108 and 106 M-1 <ref name= "Klabunde">PMID: 10742177</ref>. | Two hormone binding sites are located at the dimer–dimer region bind T4 with negative cooperativity. Under physiological conditions, the bound between the natural ligand and the tetramer can’t be broken down. Moreover, there is only one hormone bound per tetramer. The negative cooperativity mechanism explain the fact that the affinity constants (Ka) for the binding of the first and the second T4 changes, they are respectively 108 and 106 M-1 <ref name= "Klabunde">PMID: 10742177</ref>. | ||
[[Image:t4.png|thumb|left|alt=Puzzle globe|Caption for the image|Structure of thyroxine (T4)|200px]] | [[Image:t4.png|thumb|left|alt=Puzzle globe|Caption for the image|Structure of thyroxine (T4)|200px]] | ||
| Line 72: | Line 72: | ||
==== TTR-RBP complex ==== | ==== TTR-RBP complex ==== | ||
TTR is a specific carrier of retinol-binding protein (RBP). RBPs have a molecular mass of 21 kDa. They are composed of an eight-stranded β-barrel and a C-terminal α-helix. | TTR is a specific carrier of retinol-binding protein (RBP). RBPs have a molecular mass of 21 kDa. They are composed of an eight-stranded β-barrel and a C-terminal α-helix. | ||
One tetramer of TTR can bind two molecules of RBP in vitro (1:2 stoichiometry). However, when we isolate the TTR-RBP complex from the plasma (in vivo) we find a 1:1 stoichiometry <ref name= "Naylor"> "Naylor, H. M., & Newcomer, M. E. (1999). The Structure of Human Retinol-Binding Protein (RBP) with Its Carrier Protein Transthyretin Reveals an Interaction with the Carboxy Terminus of RBP†,‡. Biochemistry, 38(9), 2647–2653. doi:10.1021/bi982291i"</ref> . The β-barrel entrance loop involved in A-B strands binding (amino acids from 31 to 38, hairpin1) is also implicated in the TTR-RBP interaction. | One tetramer of TTR can bind two molecules of RBP in vitro (1:2 stoichiometry). However, when we isolate the TTR-RBP complex from the plasma (in vivo) we find a 1:1 stoichiometry <ref name= "Naylor"> "Naylor, H. M., & Newcomer, M. E. (1999). The Structure of Human Retinol-Binding Protein (RBP) with Its Carrier Protein Transthyretin Reveals an Interaction with the Carboxy Terminus of RBP†,‡. Biochemistry, 38(9), 2647–2653. doi:http://dx.doi.org/10.1021/bi982291i"</ref> . The β-barrel entrance loop involved in A-B strands binding (amino acids from 31 to 38, hairpin1) is also implicated in the TTR-RBP interaction. | ||
RBP-TTR complex stale at high ionic strength and dissociate at low ionic strength <ref name ="Zanetti">Zanotti, G., Ottonello, S., Berni, R., & Monaco, H. L. (1993). Crystal Structure of the Trigonal Form of Human Plasma Retinol-binding Protein at 2·5 Å Resolution. Journal of Molecular Biology, 230(2), 613–624. doi:10.1006/jmbi.1993.1173 </ref>. It is explained by the presence of a hydrophobic surface in the contact region, represented by hairpin 1,2,3 (include Leu35, 63, 64 and 67). Trp67 (close to hairpin1) seems to be involved in the binding<ref name="Zanetti"/>. The dissociation constant of this complex is around 0.4 µM <ref name= "Naylor"/>. | RBP-TTR complex stale at high ionic strength and dissociate at low ionic strength <ref name ="Zanetti">Zanotti, G., Ottonello, S., Berni, R., & Monaco, H. L. (1993). Crystal Structure of the Trigonal Form of Human Plasma Retinol-binding Protein at 2·5 Å Resolution. Journal of Molecular Biology, 230(2), 613–624. doi: http://dx.doi.org/10.1006/jmbi.1993.1173 </ref>. It is explained by the presence of a hydrophobic surface in the contact region, represented by hairpin 1,2,3 (include Leu35, 63, 64 and 67). Trp67 (close to hairpin1) seems to be involved in the binding<ref name="Zanetti"/>. The dissociation constant of this complex is around 0.4 µM <ref name= "Naylor"/>. | ||
[[Image:images.png|thumb|left|alt=Puzzle globe|Caption for the image|Human RBP : Human TTR structure in "opposite dimer" model|200px]] | [[Image:images.png|thumb|left|alt=Puzzle globe|Caption for the image|Human RBP : Human TTR structure in "opposite dimer" model|200px]] | ||
| Line 82: | Line 82: | ||
== Disease == | == Disease == | ||
The most known defect related to TTR is the formation of amyloid fibrils, which can engender several diseases such as familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and senile systemic amyloidosis (SSA) also called wild-type transthyretin amyloid (WTTA or ATTR)<ref> Faria TQ, Almeida ZL, Cruz PF, Jesus CS, Castanheira P, Brito RM. A look into amyloid formation by transthyretin: aggregation pathway and a novel kinetic model. Phys Chem Chem Phys. 2015 Mar 4;17(11):7255-63 | The most known defect related to TTR is the formation of amyloid fibrils, which can engender several diseases such as familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and senile systemic amyloidosis (SSA) also called wild-type transthyretin amyloid (WTTA or ATTR)<ref> Faria TQ, Almeida ZL, Cruz PF, Jesus CS, Castanheira P, Brito RM. A look into amyloid formation by transthyretin: aggregation pathway and a novel kinetic model. Phys Chem Chem Phys. 2015 Mar 4;17(11):7255-63. PMID:25694367 doi:http://dx.doi.org/10.1039/c4cp04549a </ref>. Another type of disease possibly engendered due to TTR amyloid fibrils is the central nervous system selective amyloidosis (CNSA) including familial oculoleptomeningeal amyloidosis characterized by an eye injury, or meningocerebrovascular amyloidosis if the eye is not affected. <ref> P.Gambetti, C. Russo. Human brain amyloidoses. Neuphrol Dial Transplant. 1998; 13 [Suppl 7] : 33-40</ref> | ||