Amyloid formation by the model protein muscle acylphosphatase is accelerated by heparin and heparan sulphate through a scaffolding-based mechanism.
Amyloid formation is the hallmark of many diseases. The propensity of a protein to aggregate depends on a number of biological factors like the presence of sulphated polysaccharides termed as glycosaminoglycans (GAGs). Here we assessed whether the polymeric nature of GAGs is responsible for their protein aggregation-promoting effect. We studied the effect of different monosaccharide derivatives, featuring the main characteristics of heparin and heparan sulphate (HS) building blocks, on the aggregation kinetics of human muscle acylphosphatase (mAcP), a useful model protein for these studies. We observed that while heparin and HS changed the mAcP aggregation kinetic profile, the monosaccharide derivatives had no effect, whatever their concentration could be and both when they are studied separately or in combination. In contrast, heparin fragments with six or more monosaccharides reproduced the effects of HS and in part those of heparin. We conclude that the effect of heparin and HS on protein aggregation arises from the clustering and regular distribution of their composing units on a polymeric structure. We propose a model in which heparin and HS promote mAcP aggregation through a scaffolding-based mechanism, in which the regularly spaced sulphate moieties of the polymer interact with mAcP molecules increasing their local concentration and facilitating their orientation.
Motamedi-Shad
Neda
N
Dipartimento di Scienze Biochimiche, Università di Firenze, Viale Morgagni, 50, 50134 Firenze; and Consorzio interuniversitario "Istituto Nazionale Biostrutture e Biosistemi" (INBB), Viale delle Medaglie d'Oro, 305, 00136 Roma, Italy.
Monsellier
Elodie
E
Chiti
Fabrizio
F
D017766:Acid Anhydride Hydrolases / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006025:Glycosaminoglycans / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D009124:Muscle Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D013552:Swine; D000097024:Acylphosphatase
D017766:Acid Anhydride Hydrolases; D000682:Amyloid; D005343:Fibrinolytic Agents; D006025:Glycosaminoglycans; D006493:Heparin; D006497:Heparan Sulfate; D009124:Muscle Proteins; D000097024:Acylphosphatase