Amyloids are implicated in neurodegenerative diseases. Fibrillar aggregates of the amyloid-β protein (Aβ) are the main component of the senile plaques found in brains of Alzheimer's disease patients. We present the structure of an Aβ(1-42) fibril composed of two intertwined protofilaments determined by cryo-electron microscopy (cryo-EM) to 4.0-angstrom resolution, complemented by solid-state nuclear magnetic resonance experiments. The backbone of all 42 residues and nearly all side chains are well resolved in the EM density map, including the entire N terminus, which is part of the cross-β structure resulting in an overall "LS"-shaped topology of individual subunits. The dimer interface protects the hydrophobic C termini from the solvent. The characteristic staggering of the nonplanar subunits results in markedly different fibril ends, termed "groove" and "ridge," leading to different binding pathways on both fibril ends, which has implications for fibril growth.

In idiopathic Parkinson's disease, intracytoplasmic neuronal inclusions (Lewy bodies) containing aggregates of the protein ␣-synuclein (␣S) are deposited in the pigmented nuclei of the brainstem. The mechanisms underlying the structural transition of innocuous, presumably natively unfolded, ␣S to neurotoxic forms are largely unknown. Using paramagnetic relaxation enhancement and NMR dipolar couplings, we show that monomeric ␣S assumes conformations that are stabilized by long-range interactions and act to inhibit oligomerization and aggregation. The autoinhibitory conformations fluctuate in the range of nanoseconds to microseconds corresponding to the time scale of secondary structure formation during folding. Polyamine binding and͞or temperature increase, conditions that induce aggregation in vitro, release this inherent tertiary structure, leading to a completely unfolded conformation that associates readily. Stabilization of the native, autoinhibitory structure of ␣S constitutes a potential strategy for reducing or inhibiting oligomerization and aggregation in Parkinson's disease.is the second most common neurodegenerative disease and the most common movement disorder, affecting 1-2% of the population over 65 years of age (1). The cause of PD is as yet unclear due in part to a complex etiology involving a combination of genetic susceptibility and numerous environmental factors (2). Proteinaceous aggregates in motor neurons of the substantia nigra and locus coeruleus are characteristic of idiopathic PD. An abundant component of these so-called Lewy bodies is the presynaptic protein ␣-synuclein (␣S) (3). Three genetic mutations in ␣S (A30P, E46K and A53T) have been identified in autosomal-dominantly inherited early-onset PD (4, 5). In vitro, different conditions such as increased temperature, lower pH, and naturally occurring polyamines accelerate ␣S aggregation (6, 7). Compelling evidence now supports a cytotoxic role in PD for protofibrils, early oligomers of ␣S (8).In other amyloid-related neurological disorders, such as Creutzfeldt-Jakob disease, protein oligomerization͞aggregation requires destabilization of a soluble monomeric protein followed by the formation of highly ordered, ␤-sheet-like fibrillar structures (9). ␣S, however, belongs to the class of natively unfolded proteins with no apparent ordered secondary structure detectable by far-UV CD, Fourier transform IR, or NMR spectroscopy (6, 10, 11), although recent evidence indicates the existence of distinct, functionally relevant intramolecular interactions (refs. 7 and 12 and this work). The challenge is to rationalize in structural terms the inactive state of the soluble, unstructured protein and the potentiation of aggregation by point mutations, ligand binding, or changes in solution conditions. During the past decade numerous NMR techniques have been developed for elucidating the unfolded states of proteins in atomic detail (13). 15 N-relaxation time measurements and paramagnetic relaxation enhancement (PRE) from site-directed spin labeling allo...