3 research outputs found
Fine Mapping of the Amyloid β‑Protein Binding Site on Myelin Basic Protein
The
assembly and deposition of amyloid β-protein (Aβ) in brain
is a key pathological feature of Alzheimer’s disease and related
disorders. Factors have been identified that can either promote or
inhibit Aβ assembly in brain. We previously reported that myelin
basic protein (MBP) is a potent inhibitor of Aβ fibrillar assembly
[Hoos, M. D., et al. (2007) <i>J. Biol. Chem. 282</i>, 9952–9961;
Hoos, M. D., et al. (2009) <i>Biochemistry 48</i>, 4720–4727].
Moreover, the region on MBP responsible for this activity was localized
to the 64 N-terminal amino acids (MBP<sub>1–64</sub>) [Liao,
M. C., et al. (2010) <i>J. Biol. Chem. 285</i>, 35590–35598].
In the study presented here, we sought to further define the site
on MBP<sub>1–64</sub> involved in this activity. Deletion mapping
studies showed that the C-terminal region (residues 54–64)
is required for the ability of MBP<sub>1–64</sub> to bind Aβ
and inhibit fibril assembly. Alanine scanning mutagenesis revealed
that amino acids K54, R55, G56, and K59 within MBP<sub>1–64</sub> are important for both Aβ binding and inhibition of fibril
assembly as assessed by solid phase binding, thioflavin T binding
and fluorescence, and transmission electron microscopy studies. Strong
spectral shifts are observed by solution nuclear magnetic resonance
spectroscopy of specific N-terminal residues (E3, R5, D7, E11, and
Q15) of Aβ42 upon the interaction with MBP<sub>1–64</sub>. Although the C-terminal region of MBP<sub>1–64</sub> is
required for interactions with Aβ, a synthetic MBP<sub>50–64</sub> peptide was itself devoid of activity. These studies identify key
residues in MBP and Aβ involved in their interactions and provide
structural insight into how MBP regulates Aβ fibrillar assembly