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Computer-based screening of functional conformers of proteins.

ABSTRACT: A long-standing goal in biology is to establish the link between function, structure, and dynamics of proteins. Considering that protein function at the molecular level is understood by the ability of proteins to bind to other molecules, the limited structural data of proteins in association with other bio-molecules represents a major hurdle to understanding protein function at the structural level. Recent reports show that protein function can be linked to protein structure and dynamics through network centrality analysis, suggesting that the structures of proteins bound to natural ligands may be inferred computationally. In the present work, a new method is described to discriminate protein conformations relevant to the specific recognition of a ligand. The method relies on a scoring system that matches critical residues with central residues in different structures of a given protein. Central residues are the most traversed residues with the same frequency in networks derived from protein structures. We tested our method in a set of 24 different proteins and more than 260,000 structures of these in the absence of a ligand or bound to it. To illustrate the usefulness of our method in the study of the structure/dynamics/function relationship of proteins, we analyzed mutants of the yeast TATA-binding protein with impaired DNA binding. Our results indicate that critical residues for an interaction are preferentially found as central residues of protein structures in complex with a ligand. Thus, our scoring system effectively distinguishes protein conformations relevant to the function of interest.

SUBMITTER: Montiel Molina HM

PROVIDER: S-EPMC2265533 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Computer-based screening of functional conformers of proteins.

Montiel Molina Héctor Marlosti HM Millán-Pacheco César C Pastor Nina N del Rio Gabriel G

PLoS computational biology 20080229 2

A long-standing goal in biology is to establish the link between function, structure, and dynamics of proteins. Considering that protein function at the molecular level is understood by the ability of proteins to bind to other molecules, the limited structural data of proteins in association with other bio-molecules represents a major hurdle to understanding protein function at the structural level. Recent reports show that protein function can be linked to protein structure and dynamics through ...[more]

PMID: 18463705

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Project description:UNLABELLED:Despite the demonstration that amyloid-? (A?) can trigger increased tau phosphorylation and neurofibrillary tangle (NFT) formation in vivo, the molecular link associating A? and tau pathologies remains ill defined. Here, we observed that exposure of cultured primary neurons to A? trimers isolated from brain tissue of subjects with Alzheimer's disease led to a specific conformational change of tau detected by the antibody Alz50. A similar association was supported by postmortem human brain analyses. To study the role of A? trimers in vivo, we created a novel bigenic Tg-A?+Tau mouse line by crossing Tg2576 (Tg-A?) and rTg4510 (Tg-Tau) mice. Before neurodegeneration and amyloidosis, apparent A? trimers were increased by ?2-fold in 3-month-old Tg-A? and Tg-A?+Tau mice compared with younger mice, whereas soluble monomeric A? levels were unchanged. Under these conditions, the expression of soluble Alz50-tau conformers rose by ?2.2-fold in the forebrains of Tg-A?+Tau mice compared with nontransgenic littermates. In parallel, APP accumulated intracellularly, suggestive of a putative dysfunction of anterograde axonal transport. We found that the protein abundance of the kinesin-1 light chain (KLC1) was reduced selectively in vivo and in vitro when soluble A? trimers/Alz50-tau were present. Importantly, the reduction in KLC1 was prevented by the intraneuronal delivery of Alz50 antibodies. Collectively, our findings reveal that specific soluble conformers of A? and tau cooperatively disrupt axonal transport independently from plaques and tangles. Finally, these results suggest that not all endogenous A? oligomers trigger the same deleterious changes and that the role of each assembly should be considered separately. SIGNIFICANCE STATEMENT:The mechanistic link between amyloid-? (A?) and tau, the two major proteins composing the neuropathological lesions detected in brain tissue of Alzheimer's disease subjects, remains unclear. Here, we report that the trimeric A? species induce a pathological modification of tau in cultured neurons and in bigenic mice expressing A? and human tau. This linkage was also observed in postmortem brain tissue from subjects with mild cognitive impairment, when A? trimers are abundant. Further, this modification of tau was associated with the intracellular accumulation of the precursor protein of A?, APP, as a result of the selective decrease in kinesin light chain 1 expression. Our findings suggest that A? trimers might cause axonal transport deficits in AD.

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Computer-based screening of functional conformers of proteins.

Publications

Computer-based screening of functional conformers of proteins.

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