Serag AA, Altenbach C, Gingery M, Hubbell WL, Yeates TO.
Arrangement of subunits and ordering of beta-strands in an amyloid sheet.
Nat Struct Biol. 2002 Oct;9(10):734-9.
PubMed.
Serag et al. report the results of site-directed spin labeling (SDSL) studies of inter-residue distances in native and amyloid-associated forms of transthyretin (TTR). TTR is associated with a number of amyloidoses, including senile systemic amyloidosis and familial amyloid polyneuropathy. The findings are of interest both for understanding the formation of amyloid fibrils by TTR and for understanding basic features of protein folding and design. An important question in this latter area is why proteins with high native b-sheet content do not assemble into amyloid. A systematic investigation into this question (Richardson and Richardson, 2002) revealed that protein evolution has resulted in the inclusion of structural elements in natively folded proteins that "protect" edge β-strands from interactions with neighboring strands that might lead to adventitious and pathologic β-sheet formation. Typically, this type of protection is provided in cis by amino acid sequence elements in the edge strand that inhibit or preclude inter-strand interactions. A second major design is in transprotection, i.e., the allosteric protection of edge strands through their sequestration "under" associated helices, loops, or other structural elements.
In TTR, the studies of Serag et al. suggest that amyloid fibril assembly occurs when one edge strand (the C/C'-strand) moves, exposing the penultimate strand (B/B'-strand) "below" and allowing its homotypic interaction with a similarly exposed neighboring strand in the TTR tetramer. This finding suggests that strategies designed to provide exogenous small-molecule proxies for the erstwhile protective C/C'-strands might have clinical merit in the treatment of TTR amyloidoses. In addition, the Serag study attests to the value and power of SDSL for examination of the spatial arrangement of amino acids within peptides and proteins with propensities for amyloid formation.
One area not addressed in this work is the mechanism of formation of amyloids by peptides that normally exist as portions of larger proteins, e.g., the Aβ peptide and the BRI proteins ABri and ADan. The mechanism preventing these proteins from assembling is quite simple, as they exist natively as parts of the polypeptide chains of their precursor proteins. Understanding the conformational changes necessary for amyloid formation in these cases may be a little harder than for TTR and other natively folded proteins. Nevertheless, the SDSL approach offers a viable method for improving our understanding of the topological features of amyloid formation for these proteins. It should also be noted that because all amyloid proteins share the property of forming extended β-sheets, an "edge-directed" therapeutic approach may also be of value for proteins like Aβ et al.
References:
Richardson JS, Richardson DC.
Natural beta-sheet proteins use negative design to avoid edge-to-edge aggregation.
Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2754-9.
PubMed.
Comments
David Geffen School of Medicine at UCLA
Serag et al. report the results of site-directed spin labeling (SDSL) studies of inter-residue distances in native and amyloid-associated forms of transthyretin (TTR). TTR is associated with a number of amyloidoses, including senile systemic amyloidosis and familial amyloid polyneuropathy. The findings are of interest both for understanding the formation of amyloid fibrils by TTR and for understanding basic features of protein folding and design. An important question in this latter area is why proteins with high native b-sheet content do not assemble into amyloid. A systematic investigation into this question (Richardson and Richardson, 2002) revealed that protein evolution has resulted in the inclusion of structural elements in natively folded proteins that "protect" edge β-strands from interactions with neighboring strands that might lead to adventitious and pathologic β-sheet formation. Typically, this type of protection is provided in cis by amino acid sequence elements in the edge strand that inhibit or preclude inter-strand interactions. A second major design is in transprotection, i.e., the allosteric protection of edge strands through their sequestration "under" associated helices, loops, or other structural elements.
In TTR, the studies of Serag et al. suggest that amyloid fibril assembly occurs when one edge strand (the C/C'-strand) moves, exposing the penultimate strand (B/B'-strand) "below" and allowing its homotypic interaction with a similarly exposed neighboring strand in the TTR tetramer. This finding suggests that strategies designed to provide exogenous small-molecule proxies for the erstwhile protective C/C'-strands might have clinical merit in the treatment of TTR amyloidoses. In addition, the Serag study attests to the value and power of SDSL for examination of the spatial arrangement of amino acids within peptides and proteins with propensities for amyloid formation.
One area not addressed in this work is the mechanism of formation of amyloids by peptides that normally exist as portions of larger proteins, e.g., the Aβ peptide and the BRI proteins ABri and ADan. The mechanism preventing these proteins from assembling is quite simple, as they exist natively as parts of the polypeptide chains of their precursor proteins. Understanding the conformational changes necessary for amyloid formation in these cases may be a little harder than for TTR and other natively folded proteins. Nevertheless, the SDSL approach offers a viable method for improving our understanding of the topological features of amyloid formation for these proteins. It should also be noted that because all amyloid proteins share the property of forming extended β-sheets, an "edge-directed" therapeutic approach may also be of value for proteins like Aβ et al.
References:
Richardson JS, Richardson DC. Natural beta-sheet proteins use negative design to avoid edge-to-edge aggregation. Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2754-9. PubMed.
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