title: Effect of single point mutations in a form of systemic amyloidosis.
abstract: Amyloid deposits of light-chain proteins are associated with the most common form of systemic amyloidosis. We have studied the effects of single point mutations on amyloid formation of these proteins using explicit solvent model molecular dynamics simulations. For this purpose, we compare the stability of the wild-type immunoglobulin light-chain protein REI in its native and amyloid forms with that of four mutants: R61N, G68D, D82I, and A84T. We argue that the experimentally observed differences in the propensity for amyloid formation result from two effects. First, the mutant dimers have a lower stability than the wild-type dimer due to increase exposure of certain hydrophobic residues. The second effect is a shift in equilibrium between monomers with amyloid-like structure and such with native structures. Hence, when developing drugs against light-chain associated systemic amyloidosis, one should look for components that either stabilize the dimer by binding to the dimer interface or reduce for the monomers the probability of the amyloid form.
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, 73019.
authors.forename: Manikanthan
authors.initials: M
authors.lastname: Bhavaraju
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, 73019.
authors.forename: Ulrich H E
authors.initials: UH
authors.lastname: Hansmann
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D058227:Amyloidogenic Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000686:Amyloidosis / Q000235:genetics* / Q000378:metabolism; D001536:Bence Jones Protein / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D007147:Immunoglobulin Light Chains / Q000737:chemistry; D000075363:Immunoglobulin Light-chain Amyloidosis; D008958:Models, Molecular; D017354:Point Mutation; D013816:Thermodynamics
chemical_list: D000682:Amyloid; D058227:Amyloidogenic Proteins; D007147:Immunoglobulin Light Chains; D001536:Bence Jones Protein
keywords: aggregation; light-chain proteins; molecular dynamics; systemic amyloidosis