Abstract:
:Current data suggest that globular domains may form amyloids via different mechanisms. Nevertheless, there are indications that the initiation of the process takes place invariably in the less stable segments of a protein domain. We have studied the sequence and structural conservation of beta(2)-microglobulin that deposits into fibrils in dialysis-related amyloidosis. The dataset includes 51 high-resolution non-redundant structures of the antibody constant domain-like proteins (C1) and 132 related sequences. We describe a set of 30 conserved residues. Among them, 23 are conserved structurally, 16 are conserved sequentially and nine are conserved both sequentially and structurally. Strands A (12-18), G (91-95) and D (45-55) are the less conserved and stable segments of the domain, while strands B (22-28), C (36-41), E (62-70) and F (78-83) are the conserved and stable segments. We find that the conserved residues form a cluster with a network of interactions. The observed pattern of conservation is consistent with experimental data including H/D exchange, urea denaturation and limited proteolysis that suggest that strands A and G do not participate in the amyloid fibril. Additionally, the low conservation of strand D is consistent with the observation that this strand may acquire different conformations as seen in crystal structures of bound and isolated beta(2)-microglobulin. We used a docking technique to suggest a model for a fibril via stacking of beta(2)-microglobulin monomers. Our analysis suggests that the favored monomer building block for fibril elongation is the conformation of the isolated beta(2)-microglobulin, without the beta-bulge on strand D and without strands A and G participating in the fibril beta-sheet structure. This monomer retains all the conserved residues and their network of interactions, increasing the likelihood of its existence in solution. The inter-strand interaction between the two (monomer) building blocks forms a new continuous beta-sheet such that addition of monomers results in a fibril model that has the characteristic cross-beta structure.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Benyamini H,Gunasekaran K,Wolfson H,Nussinov Rdoi
10.1016/s0022-2836(03)00557-6keywords:
subject
Has Abstractpub_date
2003-06-27 00:00:00pages
159-74issue
1eissn
0022-2836issn
1089-8638pii
S0022283603005576journal_volume
330pub_type
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