tailieunhanh - Báo cáo khoa hoc : Protein engineering to stabilize soluble amyloid b-protein aggregates for structural and functional studies

The molecular biology underlying protein aggregation and neuronal death in Alzheimer’s disease is not yet completely understood, but small soluble nonamyloid aggregates of the amyloidb-protein (Ab) have been shown to play a fundamental neurotoxic role. | IFEBS Journal REVIEW ARTICLE Protein engineering to stabilize soluble amyloid p-protein aggregates for structural and functional studies Torleif Hard Department of Molecular Biology Swedish University of AgriculturalSciences SLU Uppsala Sweden Keywords Alzheimer s disease amyloid amyloid p-protein cysteine disulfide engineering neurotoxicity oligomer protein engineering protein structure protofibril Correspondence T. Hard Department of Molecular Biology Swedish University of AgriculturalSciences SLU Box 590 SE-751 24 Uppsala Sweden Fax 0046 18 536971 Tel 0046 18 4714055 E-mail Received 14 April 2011 revised 25 July 2011 accepted 4 August 2011 doi The molecular biology underlying protein aggregation and neuronal death in Alzheimer s disease is not yet completely understood but small soluble nonamyloid aggregates of the amyloid p-protein Ab have been shown to play a fundamental neurotoxic role. The composition and biological action of such aggregates known as oligomers and protofibrils are therefore areas of intense study. However research is complicated by the multitude of different interconverting aggregates that Ap can form in vitro and in vivo and by the inhomogeneity and instability of in vitro preparations. Here we review recent studies in which protein engineering and in particular disulfide engineering has been applied to stabilize different Ap aggregates. For example several techniques now exist to obtain stable and neurotoxic pro-tofibrillar forms of Ap and engineered Ap dimers or larger aggregates formed by these have been shown to specifically induce neuronal damage in a way that mimics Alzheimer s disease pathology. Disulfide engineering has also revealed structural properties of neurotoxic aggregates for instance that Ap in protofibrils and globular oligomers adopts a p-hairpin conformation that is similar to but topologically distinct from the conformation of Ap in mature amyloid fibrils. Protein .