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Biochim Biophys Acta. 2014 Sep;1844(9):1599-607. doi: 10.1016/j.bbapap.2014.06.002. Epub 2014 Jun 11.

Toward a common aggregation mechanism for a β-barrel protein family: insights derived from a stable dimeric species.

Author information

1
Department of Biological Chemistry and Institute of Biochemistry and Biophysics (IQUIFIB), School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956, C1113AAD Buenos Aires, Argentina.
2
Instituto de Investigaciones Bioquímicas de Buenos Aires-CONICET and Laboratory of Structural Cell Biology, Leloir Institute Foundation, Av. Patricias Argentinas 435, C1405BWE Buenos Aires, Argentina; Department of Biological Chemistry-School of Sciences-University of Buenos Aires, Buenos Aires, Argentina.
3
Department of Molecular Medicine, USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; Institute for Biological Instrumentation, Russian Academy of Sciences, 142292 Pushchino, Moscow Region, Russia.
4
Department of Biological Chemistry and Institute of Biochemistry and Biophysics (IQUIFIB), School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956, C1113AAD Buenos Aires, Argentina. Electronic address: delfino@qb.ffyb.uba.ar.

Abstract

Δ78Δ is a second generation functional all-β sheet variant of IFABP (intestinal fatty acid binding protein) corresponding to the fragment 29-106 of the parent protein. This protein and its predecessor, Δ98Δ (segment 29-126 of IFABP), were initially uncovered by controlled proteolysis. Remarkably, although IFABP and Δ98Δ are monomers in solution, Δ78Δ adopts a stable dimeric structure. With the aim of identifying key structural features that modulate the aggregation of β-proteins, we evaluate here the structure and aggregation propensity of Δ78Δ. The 2,2,2-trifluoroethanol (TFE) induced aggregation of this protein shows a primary nucleation-elongation mechanism, characterized by the stabilization of a dimeric nucleus. Its rate of production from the co-solvent induced aggregation prone state governs the kinetics of polymerization. In this context, the value of Δ78Δ lies in the fact that - being a stable dimeric species - it reduces an otherwise bimolecular reaction to a unimolecular one. Interestingly, even though Δ78Δ and IFABP display similar conformational stability, the abrogated form of IFABP shows an enhanced aggregation rate, revealing the ancillary role played on this process by the free energy of the native proteins. Δ78Δ share with IFABP and Δ98Δ a common putative aggregation-prone central peptide. Differences in the exposure/accessibility of this segment dictated by the environment around this region might underlie the observed variations in the speed of aggregation. Lessons learnt from this natural dimeric protein might shed light on the early conformational events leading to β-conversion from barrels to amyloid aggregates.

KEYWORDS:

Abridged proteins; Amyloid-like aggregation; Intestinal fatty acid binding protein; Protein conformation; Trifluoroethanol; β-barrel protein

PMID:
24929115
DOI:
10.1016/j.bbapap.2014.06.002
[Indexed for MEDLINE]

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