Molecular mechanisms of fibrillogenesis and the protective role of amyloid P component: Two possible avenues for therapy
Amyloid deposits regress when the supply of fibril precursor proteins is sufficiently reduced, indicating that amyloid fibrils are degradable in vim. Serum amyloid P component (SAP), a universal constituent of amyloid deposits, efficiently protects amyloid fibrils from proteolysis in vitro, and may...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Conference item |
| Published: |
1996
|
| _version_ | 1826302891257757696 |
|---|---|
| author | Pepys, M Tennent, G Booth, DR Bellotti, V Lovat, L Tan, S Persey, MR Hutchinson, W Booth, SE Madhoo, S Soutar, A Hawkins, P VanZylSmit, R Campistol, J Fraser, P Radford, SE Robinson, C Sunde, M Serpell, L Blake, C Maeda Goldgaber Kisilevsky Buxbaum, J Westermark |
| author_facet | Pepys, M Tennent, G Booth, DR Bellotti, V Lovat, L Tan, S Persey, MR Hutchinson, W Booth, SE Madhoo, S Soutar, A Hawkins, P VanZylSmit, R Campistol, J Fraser, P Radford, SE Robinson, C Sunde, M Serpell, L Blake, C Maeda Goldgaber Kisilevsky Buxbaum, J Westermark |
| author_sort | Pepys, M |
| collection | OXFORD |
| description | Amyloid deposits regress when the supply of fibril precursor proteins is sufficiently reduced, indicating that amyloid fibrils are degradable in vim. Serum amyloid P component (SAP), a universal constituent of amyloid deposits, efficiently protects amyloid fibrils from proteolysis in vitro, and may contribute to persistence of amyloid in vivo. Drugs that prevent binding of SAP to amyloid fibrils in vivo should therefore promote regression of amyloid and we are actively seeking such agents. A complementary strategy is identification of critical molecular processes in fibrillogenesis as targets for pharmacological intervention. All amyloidogenic variants of apolipoprotein AI contain an additional positive charge in the N-terminal fibrillogenic region of the protein. This is unlikely to be a coincidence and should be informative about amyloidogenesis by this protein. The two amyloidogenic variants of human lysozyme, caused by the first natural mutations found in its gene, provide a particularly powerful model system because both the crystal structure and folding pathways of wild-type lysozyme are so well characterized. The amyloidogenic variant lysozymes have similar 3D crystal structures to the wild type, but are notably less thermostable. They unfold on heating, lose enzymic activity, and aggregate to form amyloid fibrils in vitro. |
| first_indexed | 2024-03-07T05:54:19Z |
| format | Conference item |
| id | oxford-uuid:e9fc7532-3784-46d6-a30f-b6fda43088b0 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T05:54:19Z |
| publishDate | 1996 |
| record_format | dspace |
| spelling | oxford-uuid:e9fc7532-3784-46d6-a30f-b6fda43088b02022-03-27T10:58:20ZMolecular mechanisms of fibrillogenesis and the protective role of amyloid P component: Two possible avenues for therapyConference itemhttp://purl.org/coar/resource_type/c_5794uuid:e9fc7532-3784-46d6-a30f-b6fda43088b0Symplectic Elements at Oxford1996Pepys, MTennent, GBooth, DRBellotti, VLovat, LTan, SPersey, MRHutchinson, WBooth, SEMadhoo, SSoutar, AHawkins, PVanZylSmit, RCampistol, JFraser, PRadford, SERobinson, CSunde, MSerpell, LBlake, CMaedaGoldgaberKisilevskyBuxbaum, JWestermarkAmyloid deposits regress when the supply of fibril precursor proteins is sufficiently reduced, indicating that amyloid fibrils are degradable in vim. Serum amyloid P component (SAP), a universal constituent of amyloid deposits, efficiently protects amyloid fibrils from proteolysis in vitro, and may contribute to persistence of amyloid in vivo. Drugs that prevent binding of SAP to amyloid fibrils in vivo should therefore promote regression of amyloid and we are actively seeking such agents. A complementary strategy is identification of critical molecular processes in fibrillogenesis as targets for pharmacological intervention. All amyloidogenic variants of apolipoprotein AI contain an additional positive charge in the N-terminal fibrillogenic region of the protein. This is unlikely to be a coincidence and should be informative about amyloidogenesis by this protein. The two amyloidogenic variants of human lysozyme, caused by the first natural mutations found in its gene, provide a particularly powerful model system because both the crystal structure and folding pathways of wild-type lysozyme are so well characterized. The amyloidogenic variant lysozymes have similar 3D crystal structures to the wild type, but are notably less thermostable. They unfold on heating, lose enzymic activity, and aggregate to form amyloid fibrils in vitro. |
| spellingShingle | Pepys, M Tennent, G Booth, DR Bellotti, V Lovat, L Tan, S Persey, MR Hutchinson, W Booth, SE Madhoo, S Soutar, A Hawkins, P VanZylSmit, R Campistol, J Fraser, P Radford, SE Robinson, C Sunde, M Serpell, L Blake, C Maeda Goldgaber Kisilevsky Buxbaum, J Westermark Molecular mechanisms of fibrillogenesis and the protective role of amyloid P component: Two possible avenues for therapy |
| title | Molecular mechanisms of fibrillogenesis and the protective role of amyloid P component: Two possible avenues for therapy |
| title_full | Molecular mechanisms of fibrillogenesis and the protective role of amyloid P component: Two possible avenues for therapy |
| title_fullStr | Molecular mechanisms of fibrillogenesis and the protective role of amyloid P component: Two possible avenues for therapy |
| title_full_unstemmed | Molecular mechanisms of fibrillogenesis and the protective role of amyloid P component: Two possible avenues for therapy |
| title_short | Molecular mechanisms of fibrillogenesis and the protective role of amyloid P component: Two possible avenues for therapy |
| title_sort | molecular mechanisms of fibrillogenesis and the protective role of amyloid p component two possible avenues for therapy |
| work_keys_str_mv | AT pepysm molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT tennentg molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT boothdr molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT bellottiv molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT lovatl molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT tans molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT perseymr molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT hutchinsonw molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT boothse molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT madhoos molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT soutara molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT hawkinsp molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT vanzylsmitr molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT campistolj molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT fraserp molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT radfordse molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT robinsonc molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT sundem molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT serpelll molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT blakec molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT maeda molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT goldgaber molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT kisilevsky molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT buxbaumj molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy AT westermark molecularmechanismsoffibrillogenesisandtheprotectiveroleofamyloidpcomponenttwopossibleavenuesfortherapy |