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Mapping the conformational variability in mutants of the amyloid precursor protein intracellular domain

Mandal, Nabanita LU and Skepö, Marie LU orcid (2026) In Journal of Molecular Biology 438(14).
Abstract

The amyloid precursor protein intracellular domain (AICD) is an intrinsically disordered regulatory segment whose conserved YENPTY motif mediates transient interactions with multiple adaptor and signaling proteins. How sequence perturbations within this motif modulate its accessibility and interaction potential within a disordered ensemble remains poorly understood. Here, we combine small-angle X-ray scattering, synchrotron radiation circular dichroism, and extensive atomistic molecular dynamics simulations to characterize conformational variability in three designed AICD variants (Y22G, T26A, and Y27A) that preserve overall charge while selectively altering local side-chain chemistry. All variants remain intrinsically disordered, yet... (More)

The amyloid precursor protein intracellular domain (AICD) is an intrinsically disordered regulatory segment whose conserved YENPTY motif mediates transient interactions with multiple adaptor and signaling proteins. How sequence perturbations within this motif modulate its accessibility and interaction potential within a disordered ensemble remains poorly understood. Here, we combine small-angle X-ray scattering, synchrotron radiation circular dichroism, and extensive atomistic molecular dynamics simulations to characterize conformational variability in three designed AICD variants (Y22G, T26A, and Y27A) that preserve overall charge while selectively altering local side-chain chemistry. All variants remain intrinsically disordered, yet each mutation induces a distinct redistribution of conformational populations. Y22G and T26A increase local flexibility and solvent exposure around the YENPTY motif and enhance motif-centered interaction propensities, whereas Y27A favors more compact conformations with reduced motif accessibility. Contact and network analyses reveal that these local perturbations propagate across the chain, reshaping long-range intramolecular coupling within the ensemble. Our results demonstrate that local changes in side-chain chemistry within YENPTY can tune motif accessibility and interaction potential through population shifts in a disordered ensemble, without stabilizing persistent secondary or tertiary structure.

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author
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Contribution to journal
publication status
published
subject
in
Journal of Molecular Biology
volume
438
issue
14
article number
169806
publisher
Elsevier
external identifiers
  • scopus:105037092963
  • pmid:41967599
ISSN
0022-2836
DOI
10.1016/j.jmb.2026.169806
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2026 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/
id
29d8370d-380d-4701-aa97-f6751ce23575
date added to LUP
2026-05-20 15:13:04
date last changed
2026-09-25 07:06:58
@article{29d8370d-380d-4701-aa97-f6751ce23575,
  abstract     = {{<p>The amyloid precursor protein intracellular domain (AICD) is an intrinsically disordered regulatory segment whose conserved YENPTY motif mediates transient interactions with multiple adaptor and signaling proteins. How sequence perturbations within this motif modulate its accessibility and interaction potential within a disordered ensemble remains poorly understood. Here, we combine small-angle X-ray scattering, synchrotron radiation circular dichroism, and extensive atomistic molecular dynamics simulations to characterize conformational variability in three designed AICD variants (Y22G, T26A, and Y27A) that preserve overall charge while selectively altering local side-chain chemistry. All variants remain intrinsically disordered, yet each mutation induces a distinct redistribution of conformational populations. Y22G and T26A increase local flexibility and solvent exposure around the YENPTY motif and enhance motif-centered interaction propensities, whereas Y27A favors more compact conformations with reduced motif accessibility. Contact and network analyses reveal that these local perturbations propagate across the chain, reshaping long-range intramolecular coupling within the ensemble. Our results demonstrate that local changes in side-chain chemistry within YENPTY can tune motif accessibility and interaction potential through population shifts in a disordered ensemble, without stabilizing persistent secondary or tertiary structure.</p>}},
  author       = {{Mandal, Nabanita and Skepö, Marie}},
  issn         = {{0022-2836}},
  language     = {{eng}},
  number       = {{14}},
  publisher    = {{Elsevier}},
  series       = {{Journal of Molecular Biology}},
  title        = {{Mapping the conformational variability in mutants of the amyloid precursor protein intracellular domain}},
  url          = {{http://dx.doi.org/10.1016/j.jmb.2026.169806}},
  doi          = {{10.1016/j.jmb.2026.169806}},
  volume       = {{438}},
  year         = {{2026}},
}