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Unraveling the conformational landscape of amyloid precursor protein intracellular domain

Mandal, Nabanita LU and Skepö, Marie LU orcid (2025) In Biophysical Journal 124(21). p.3527-3541
Abstract

The amyloid precursor protein intracellular domain (AICD), a cleavage product of amyloid precursor protein implicated in Alzheimer disease and amyloid lateral sclerosis, is a functionally important but structurally elusive intrinsically disordered protein. In this study, we investigate the conformational ensemble of a 35-residue AICD segment encompassing the conserved YENPTY motif using molecular dynamics simulations, small-angle x-ray scattering, circular dichroism, and nuclear magnetic resonance data. Our results reveal that AICD fluctuates between compact and extended states, exhibiting dynamic secondary structure elements and heterogeneous solvent accessibility. Small-angle x-ray scattering and circular dichroism analyses support a... (More)

The amyloid precursor protein intracellular domain (AICD), a cleavage product of amyloid precursor protein implicated in Alzheimer disease and amyloid lateral sclerosis, is a functionally important but structurally elusive intrinsically disordered protein. In this study, we investigate the conformational ensemble of a 35-residue AICD segment encompassing the conserved YENPTY motif using molecular dynamics simulations, small-angle x-ray scattering, circular dichroism, and nuclear magnetic resonance data. Our results reveal that AICD fluctuates between compact and extended states, exhibiting dynamic secondary structure elements and heterogeneous solvent accessibility. Small-angle x-ray scattering and circular dichroism analyses support a partially compact, flexible ensemble, whereas time-lagged independent component analysis uncovers metastable conformational states. Residue-specific solvent accessibility and hydrogen bonding patterns highlight transient structural stabilization, particularly within the YENPTY motif. These findings highlight the structural plasticity of AICD and offer insights into its potential for interaction and regulatory roles in nuclear signaling and neurodegeneration.

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type
Contribution to journal
publication status
published
subject
in
Biophysical Journal
volume
124
issue
21
pages
15 pages
publisher
Cell Press
external identifiers
  • pmid:40817583
  • scopus:105014601141
ISSN
0006-3495
DOI
10.1016/j.bpj.2025.08.010
language
English
LU publication?
yes
id
75efc1f5-b4fe-4360-bd7d-0d3fb63cd06e
date added to LUP
2025-11-17 10:18:14
date last changed
2025-11-17 10:19:03
@article{75efc1f5-b4fe-4360-bd7d-0d3fb63cd06e,
  abstract     = {{<p>The amyloid precursor protein intracellular domain (AICD), a cleavage product of amyloid precursor protein implicated in Alzheimer disease and amyloid lateral sclerosis, is a functionally important but structurally elusive intrinsically disordered protein. In this study, we investigate the conformational ensemble of a 35-residue AICD segment encompassing the conserved YENPTY motif using molecular dynamics simulations, small-angle x-ray scattering, circular dichroism, and nuclear magnetic resonance data. Our results reveal that AICD fluctuates between compact and extended states, exhibiting dynamic secondary structure elements and heterogeneous solvent accessibility. Small-angle x-ray scattering and circular dichroism analyses support a partially compact, flexible ensemble, whereas time-lagged independent component analysis uncovers metastable conformational states. Residue-specific solvent accessibility and hydrogen bonding patterns highlight transient structural stabilization, particularly within the YENPTY motif. These findings highlight the structural plasticity of AICD and offer insights into its potential for interaction and regulatory roles in nuclear signaling and neurodegeneration.</p>}},
  author       = {{Mandal, Nabanita and Skepö, Marie}},
  issn         = {{0006-3495}},
  language     = {{eng}},
  number       = {{21}},
  pages        = {{3527--3541}},
  publisher    = {{Cell Press}},
  series       = {{Biophysical Journal}},
  title        = {{Unraveling the conformational landscape of amyloid precursor protein intracellular domain}},
  url          = {{http://dx.doi.org/10.1016/j.bpj.2025.08.010}},
  doi          = {{10.1016/j.bpj.2025.08.010}},
  volume       = {{124}},
  year         = {{2025}},
}