2LZ4

Solution NMR structure of transmembrane domain of amyloid precursor protein V44M

Summary for 2LZ4

• Entry DOI: 10.2210/pdb2lz4/pdb
• Related: 2LZ3
• NMR Information: BMRB: 18648
• Descriptor: Amyloid beta A4 protein (1 entity in total)
• Functional Keywords: helix, dimer, transmembrane, membrane protein
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P05067
• Total number of polymer chains: 2
• Total formula weight: 6350.32

Authors

Chen, W.,Wang, C. (deposition date: 2012-09-23, release date: 2013-10-02, Last modification date: 2024-05-15)

Primary citation

Chen, W.,Gamache, E.,Rosenman, D.J.,Xie, J.,Lopez, M.M.,Li, Y.M.,Wang, C.
Familial Alzheimer's mutations within APPTM increase A beta 42 production by enhancing accessibility of epsilon-cleavage site.
Nat Commun, 5:3037-3037, 2014

PubMed Abstract: The high Aβ42/Aβ40 production ratio is a hallmark of familial Alzheimer's disease, which can be caused by mutations in the amyloid precursor protein (APP). The C-terminus of Aβ is generated by γ-secretase cleavage within the transmembrane domain of APP (APPTM), a process that is primed by an initial ε-cleavage at either T48 or L49, resulting in subsequent production of Aβ42 or Aβ40, respectively. Here we solve the dimer structures of wild-type APPTM (AAPTM WT) and mutant APPTM (FAD mutants V44M) with solution NMR. The right-handed APPTM helical dimer is mediated by GXXXA motif. From the NMR structural and dynamic data, we show that the V44M and V44A mutations can selectively expose the T48 site by weakening helical hydrogen bonds and increasing hydrogen-deuterium exchange rate (kex). We propose a structural model in which FAD mutations (V44M and V44A) can open the T48 site γ-secretase for the initial ε-cleavage, and consequently shift cleavage preference towards Aβ42.

PubMed: 24390130
DOI: 10.1038/ncomms4037

Experimental method

SOLUTION NMR