20 aprile 2015

articolo postato il: 2015-04-20 16:00:15

Pubblicata su JBC una review di Stoppini e Bellotti che ripercorre i progressi più significativi fatti dalla ricerca sulle basi molecolari dell`amilodosi causata da ß2-microglobulina da quando fu scoperta dal Prof Geyo.

La Figura 3 della review propone un modello di amiloidogenesi in vivo che potrebbe essere valido anche per altre proteine globulari.

Systemic Amyloidosis: Lessons from β2-Microglobulin.

Stoppini M, Bellotti V.

J Biol Chem. 2015 Apr 17;290(16):9951-9958

 

 

Schematic picture of the hypothetical events occurring in the interstitial space where globular soluble proteins undergo fibrillar conversion.

The chemical physical characteristics of the interstitial space and forces generated by the fluid flow are well reviewed in Swartz (Ann. Rev. Biomed. Eng. 9, 229-256, 2007).Native globular proteins flow through a network of fibrous proteins (i.e collagen, elastin) and GAGs. These matrix proteins expose hydrophobic patches with which the native globular proteins collide. At the interface between the hydrophobic surface and the aqueous fluid, proteins are exposed to forces sufficient to perturb the folded state.The hydrophobic force (FHydro) acting on the molecule can be calculated according to Mangione et al. (J. Biol. Chem. 288, 30917-30930, 2013) through the equation:

FHydro = – (É—EHydro/É—d)= (– 2*ϒ (a – a0) exp (– d/Dhydro))/ Dhydro

EHydro represents the hydrophobic interaction energies between two apolar surfaces, ϒ is the interfacial tension, d is the distance between the two surfaces, a is the exposed area of the molecule at distance d, a0is the optimum exposed area of the molecule, which we consider to be equal to the area of one amino acid, and Dhydro is the hydrophobic decay length. The exposure of normally buried hydrophobic elements further facilitates the interaction with the hydrophobic matrix, local accumulation of partially folded globular conformers reaching a condition of supersaturation. Supersaturation is the pre-condition for protein aggregation and loss of solubility. Even minimal changes in the intensity of the shear flow can break the very labile soluble state of partially folded proteins when they reach the condition of supersaturation. If supersaturation is not reached the simple unfolding of the proteins does not imply a fibrillar conversion and the protein can properly refold and escape from the aggregation.

 

figura 3