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Thermodynamic selection of steric zipper patterns in the amyloid cross-beta spine.

ABSTRACT: At the core of amyloid fibrils is the cross-beta spine, a long tape of beta-sheets formed by the constituent proteins. Recent high-resolution x-ray studies show that the unit of this filamentous structure is a beta-sheet bilayer with side chains within the bilayer forming a tightly interdigitating "steric zipper" interface. However, for a given peptide, different bilayer patterns are possible, and no quantitative explanation exists regarding which pattern is selected or under what condition there can be more than one pattern observed, exhibiting molecular polymorphism. We address the structural selection mechanism by performing molecular dynamics simulations to calculate the free energy of incorporating a peptide monomer into a beta-sheet bilayer. We test filaments formed by several types of peptides including GNNQQNY, NNQQ, VEALYL, KLVFFAE and STVIIE, and find that the patterns with the lowest binding free energy correspond to available atomistic structures with high accuracy. Molecular polymorphism, as exhibited by NNQQ, is likely because there are more than one most stable structures whose binding free energies differ by less than the thermal energy. Detailed analysis of individual energy terms reveals that these short peptides are not strained nor do they lose much conformational entropy upon incorporating into a beta-sheet bilayer. The selection of a bilayer pattern is determined mainly by the van der Waals and hydrophobic forces as a quantitative measure of shape complementarity among side chains between the beta-sheets. The requirement for self-complementary steric zipper formation supports that amyloid fibrils form more easily among similar or same sequences, and it also makes parallel beta-sheets generally preferred over anti-parallel ones. But the presence of charged side chains appears to kinetically drive anti-parallel beta-sheets to form at early stages of assembly, after which the bilayer formation is likely driven by energetics.

SUBMITTER: Park J

PROVIDER: S-EPMC2723932 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Thermodynamic selection of steric zipper patterns in the amyloid cross-beta spine.

Park Jiyong J Kahng Byungnam B Hwang Wonmuk W

PLoS computational biology 20090904 9

At the core of amyloid fibrils is the cross-beta spine, a long tape of beta-sheets formed by the constituent proteins. Recent high-resolution x-ray studies show that the unit of this filamentous structure is a beta-sheet bilayer with side chains within the bilayer forming a tightly interdigitating "steric zipper" interface. However, for a given peptide, different bilayer patterns are possible, and no quantitative explanation exists regarding which pattern is selected or under what condition ther ...[more]

PMID: 19730673

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Project description:BackgroundAlzheimer's disease (AD) is the most common neurodegenerative disease worldwide but has no effective treatment. Amyloid beta (Aβ) protein, a primary risk factor for AD, accumulates and aggregates in the brain of patients with AD. Paired immunoglobulin-like receptor B (PirB) has been identified as a receptor of Aβ and Aβ-PirB molecular interactions that cause synapse elimination and synaptic dysfunction. PirB deletion has been shown to suppress Aβ-induced synaptic dysfunction and behavioral deficits in AD model mice, implying that PirB mediates Aβ-induced AD pathology. Therefore, inhibiting the Aβ-PirB molecular interaction could be a successful approach for combating AD pathology. We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of type1 Nogo receptor and PirB and that LOTUS overexpression promotes neuronal regeneration following damage to the central nervous system, including spinal cord injury and ischemic stroke. Therefore, in this study, we investigated whether LOTUS inhibits Aβ-PirB interaction and Aβ-induced dendritic spine elimination.MethodsThe inhibitory role of LOTUS against Aβ-PirB (or leukocyte immunoglobulin-like receptor subfamily B member 2: LilrB2) binding was assessed using a ligand-receptor binding assay in Cos7 cells overexpressing PirB and/or LOTUS. We assessed whether LOTUS inhibits Aβ-induced intracellular alterations and synaptotoxicity using immunoblots and spine imaging in a primary cultured hippocampal neuron.ResultsWe found that LOTUS inhibits the binding of Aβ to PirB overexpressed in Cos7 cells. In addition, we found that Aβ-induced dephosphorylation of cofilin and Aβ-induced decrease in post-synaptic density-95 expression were suppressed in cultured hippocampal neurons from LOTUS-overexpressing transgenic (LOTUS-tg) mice compared with that in wild-type mice. Moreover, primary cultured hippocampal neurons from LOTUS-tg mice improved the Aβ-induced decrease in dendritic spine density. Finally, we studied whether human LOTUS protein inhibits Aβ binding to LilrB2, a human homolog of PirB, and found that human LOTUS inhibited the binding of Aβ to LilrB2 in a similar manner.ConclusionsThis study implied that LOTUS improved Aβ-induced synapse elimination by suppressing Aβ-PirB interaction in rodents and inhibited Aβ-LilrB2 interaction in humans. Our findings revealed that LOTUS may be a promising therapeutic agent in counteracting Aβ-induced AD pathologies.

Dataset Information

Thermodynamic selection of steric zipper patterns in the amyloid cross-beta spine.

Publications

Thermodynamic selection of steric zipper patterns in the amyloid cross-beta spine.

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