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Periodic Report Summary 1 - STAMYEV (Structural and biochemical basis of protein amyloid evolution)

Amyloid fibrils are protein aggregates formed by certain proteins and they underlie an increasing number of fatal diseases such as Alzheimer´s disease, Familial Amyloidotic Polyneuropathy (FAP) and atherosclerosis. Amyloid formation is an intriguing phenomenon poorly understood but found in different species through evolution from bacteria to humans. We aim to investigate how the molecular mechanisms of amyloid formation developed during the evolution of protein structures as a way to understand such mechanisms and learn strategies to prevent them.
We are using two model proteins: apolipoprotein A-I (apoA-I), a cholesterol transporter involved in atherosclerosis and familial amyloidosis, and transthyretin (TTR), a thyroid hormone transporter that forms amyloid in FAP. We are describing in detail their amyloid-formation mechanisms using mutagenesis and several biophysical methods. We are characterizing the amyloid mechanisms of apoA-I variants with single amino-acid mutations or truncations and learning how misfolding proceeds at a molecular level upon apoA-I lipid dissociation and destabilization. We have established, using TTR from fish as an evolutionary model, that amyloid mechanisms are not fully conserved in evolution: specific changes in length and properties of TTR N-terminus decreased or abolished amyloid formation. We hope to identify the specific role of the N-terminal on TTR stability and help develop ways to prevent TTR misfolding and aggregation into amyloid. Additionally, we have identified a novel amyloid-forming protein: the extracellular matrix cartilage acid protein (CRTAC) that has an unresolved structure and function but which is associated with a number of pathologies, including multiple sclerosis. We have shown that human and fish CRTAC form amyloid fibrils and we are producing the crystal structure of human, fish and bacteria CRTAC. Our goal is to help clarify CRTAC’s function and role in disease. Overall, we are contributing to a general understanding of the amyloid phenomenon and its evolution and simultaneously revealing important molecular mechanisms of amyloid formation highly relevant to identifying strategies or molecules to block this pathologic process.

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