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

ANGELANI CR; CURTO LM; CABANAS IS; CARAMELO JJ; UVERSKY VN; DELFINO JM

BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2014 vol. 0 p. 1 - 9

1570-9639

Δ78Δ is a second generation functional all-β sheet variant of IFABP (intestinal fatty acid binding protein) corre- 25 spondingtothefragment29?106oftheparentprotein.Thisproteinanditspredecessor,Δ98Δ(segment29?126 26 of IFABP), were initially uncovered by controlled proteolysis. Remarkably, although IFABP and Δ98Δ are mono- 27 mers in solution, Δ78Δ adopts a stable dimeric structure. With the aim of identifying key structural features 28 that modulate the aggregation of β-proteins, we evaluate here the structure and aggregation propensity of 29 Δ78Δ. The 2,2,2-trifluoroethanol (TFE) induced aggregation of this protein shows a primary nucleation?elonga- 30 tionmechanism,characterizedbythestabilizationofadimericnucleus.Itsrateofproductionfromtheco-solvent 31 induced aggregation prone state governs the kinetics of polymerization. In this context, the value of Δ78Δ lies in 32 the fact that ? being a stable dimeric species ? it reduces an otherwise bimolecular reaction to a unimolecular one. 33 Interestingly, even though Δ78Δ and IFABP display similar conformational stability, the abrogated form of IFABP 34 showsanenhancedaggregationrate,revealingtheancillaryroleplayedonthisprocessbythefreeenergyofthe 35 nativeproteins.Δ78ΔsharewithIFABPandΔ98Δacommonputativeaggregation-pronecentralpeptide.Differ- 36 encesintheexposure/accessibilityofthissegmentdictatedbytheenvironmentaroundthisregionmightunder- 37 lie the observed variations in the speed of aggregation. Lessons learnt from this natural dimeric protein might 38 shed light on the early conformational events leading to β-conversion from barrels to amyloid aggregates.