4JFN

Crystal structure of the N-terminal, growth factor-like domain of the amyloid precursor protein bound to copper

4JFN の概要

• エントリーDOI: 10.2210/pdb4jfn/pdb
• 分子名称: Amyloid beta A4 protein, COPPER (II) ION, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: alzheimer's disease, gfld, app, growth factor-like domain, copper binding, metal binding protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P05067
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18776.02

構造登録者

Wild, K.,Baumkotter, F.,Kins, S. (登録日: 2013-02-28, 公開日: 2014-07-23, 最終更新日: 2024-10-30)

主引用文献

Baumkotter, F.,Schmidt, N.,Vargas, C.,Schilling, S.,Weber, R.,Wagner, K.,Fiedler, S.,Klug, W.,Radzimanowski, J.,Nickolaus, S.,Keller, S.,Eggert, S.,Wild, K.,Kins, S.
Amyloid precursor protein dimerization and synaptogenic function depend on copper binding to the growth factor-like domain
J.Neurosci., 34:11159-11172, 2014

PubMed Abstract: Accumulating evidence suggests that the copper-binding amyloid precursor protein (APP) has an essential synaptic function. APP synaptogenic function depends on trans-directed dimerization of the extracellular E1 domain encompassing a growth factor-like domain (GFLD) and a copper-binding domain (CuBD). Here we report the 1.75 Å crystal structure of the GFLD in complex with a copper ion bound with high affinity to an extended hairpin loop at the dimerization interface. In coimmunoprecipitation assays copper binding promotes APP interaction, whereas mutations in the copper-binding sites of either the GFLD or CuBD result in a drastic reduction in APP cis-orientated dimerization. We show that copper is essential and sufficient to induce trans-directed dimerization of purified APP. Furthermore, a mixed culture assay of primary neurons with HEK293 cells expressing different APP mutants revealed that APP potently promotes synaptogenesis depending on copper binding to the GFLD. Together, these findings demonstrate that copper binding to the GFLD of APP is required for APP cis-/trans-directed dimerization and APP synaptogenic function. Thus, neuronal activity or disease-associated changes in copper homeostasis likely go along with altered APP synaptic function.

PubMed: 25122912
DOI: 10.1523/JNEUROSCI.0180-14.2014

実験手法

X-RAY DIFFRACTION (1.75 Å)