|
|
|
|
| LEADER |
02722 am a22002173u 4500 |
| 001 |
69052 |
| 042 |
|
|
|a dc
|
| 100 |
1 |
0 |
|a Das, Payel
|e author
|
| 100 |
1 |
0 |
|a Massachusetts Institute of Technology. Department of Biology
|e contributor
|
| 100 |
1 |
0 |
|a King, Jonathan Alan
|e contributor
|
| 100 |
1 |
0 |
|a King, Jonathan Alan
|e contributor
|
| 700 |
1 |
0 |
|a Zhou, Ruhong
|e author
|
| 700 |
1 |
0 |
|a King, Jonathan Alan
|e author
|
| 245 |
0 |
0 |
|a Aggregation of γ-crystallins associated with human cataracts via domain swapping at the C-terminal β-strands
|
| 260 |
|
|
|b Proceedings of the National Academy of Sciences (PNAS),
|c 2012-02-08T20:36:49Z.
|
| 856 |
|
|
|z Get fulltext
|u http://hdl.handle.net/1721.1/69052
|
| 520 |
|
|
|a This article contains supporting information online at www.pnas.org/lookup/suppl/ doi:10.1073/pnas.1019152108/-/DCSupplemental.
|
| 520 |
|
|
|a The prevalent eye disease age-onset cataract is associated with aggregation of human γD-crystallins, one of the longest-lived proteins. Identification of the γ-crystallin precursors to aggregates is crucial for developing strategies to prevent and reverse cataract. Our microseconds of atomistic molecular dynamics simulations uncover the molecular structure of the experimentally detected aggregation-prone folding intermediate species of monomeric native γD-crystallin with a largely folded C-terminal domain and a mostly unfolded N-terminal domain. About 30 residues including a, b, and c strands from the Greek Key motif 4 of the C-terminal domain experience strong solvent exposure of hydrophobic residues as well as partial unstructuring upon N-terminal domain unfolding. Those strands comprise the domain-domain interface crucial for unusually high stability of γD-crystallin. We further simulate the intermolecular linkage of these monomeric aggregation precursors, which reveals domain-swapped dimeric structures. In the simulated dimeric structures, the N-terminal domain of one monomer is frequently found in contact with residues 135-164 encompassing the a, b, and c strands of the Greek Key motif 4 of the second molecule. The present results suggest that γD-crystallin may polymerize through successive domain swapping of those three C-terminal β-strands leading to age-onset cataract, as an evolutionary cost of its very high stability. Alanine substitutions of the hydrophobic residues in those aggregation-prone β-strands, such as L145 and M147, hinder domain swapping as a pathway toward dimerization. These findings thus provide critical molecular insights onto the initial stages of age-onset cataract, which is important for understanding protein aggregation diseases.
|
| 546 |
|
|
|a en_US
|
| 655 |
7 |
|
|a Article
|
| 773 |
|
|
|t Proceedings of the National Academy of Sciences
|
