抄録
Transthyretin（TTR）is a plasma protein associated with human amyloid diseases. The dissociation of the TTR tetramer is considered to be the rate-limiting step in amyloid fibril formation. The amyloid fibril formation by TTR is known to be promoted by acidic pH. In order reveal the molecular mechanisms of pH dependence of TTR amyloidogenesis, the neutron crystal structure of TTR was solved at 2.0 Å resolution using IBARAKI Biological Crystal Diffractometer. The neutron structure revealed that His88 was single protonated and involved in a large hydrogen-bond network consisted of Thr75, Trp79, Pro113 and water molecules. The double protonation of His88 by acidification breaks this hydrogen-bond network and causes the destabilization of the TTR tetramer. Furthuermore, the comparison with X-ray structure solved at pH 4.0 indicated that the protonation occurred to Asp74, His88 and Glu89 at pH 4.0. Our structural analysis reveals a wealth of information about the hydrogen bonds and the pH sensitivity in human TTR.
