Histidine 31: The Achilles' heel of human tranthyretin. Microheterogeneity is not enough to understand the molecular causes of amyloidogenicity

The microheterogeneity of human transthyretin (TTR) is mainly one of ligand and amino acid substitutions. These substitutions modify the conformational stability of monomers, dimers, and tetramers and may eventually result in unfolding-refolding transitions with the endpoint of amyloidosis. In this chapter we focus on a structural peculiarity of human TTR, i.e., a hydrogen bridge between His31 (beta-strand B) and Ser46 (beta-strand C), which appears to be the vulnerable site for changes of pH within a range (pH 7.4¿6.5) observed under conditions of interstitial acidosis. We present arguments in favor of a cooperative interaction of all sites in the TTR monomer in modifying its conformational stability and reversible unfolding-refolding transitions which also affect the dimer and tetramer. We postulate that the unfolded monomer is the pool from which amyloidogenic aggregates are generated.