Molecular modeling of ARF6 dysregulation caused by mutations in IQSEC2

Michael Shokhen, Randall Walikonis, Vladimir N. Uversky, Amnon Allbeck, Camryn Zezelic, Danielle Feldman, Nina S. Levy, Andrew P. Levy

Research output: Contribution to journalArticlepeer-review

Abstract

IQSEC2 gene mutations are associated with epilepsy, autism, and intellectual disability. The primary function IQSEC2, mediated via its Sec 7 domain, is to act as a guanine nucleotide exchange factor for ARF6. We sought to develop a molecular model, which may explain the aberrant Sec 7 activity on ARF6 of different human IQSEC2 mutations. We integrated experimental data of IQSEC2 mutants with protein structure prediction by the RaptorX server combined with molecular modeling and molecular dynamics simulations. Normally, apocalmodulin (apoCM) binds to IQSEC2 resulting in its N-terminal fragment inhibiting access of its Sec 7 domain to ARF6. An increase in Ca2+ concentration destabilizes the interaction of IQSEC2 with apoCM and removes steric hindrance of Sec 7 binding with ARF6. Mutations at amino acid residue 350 of IQSEC2 result in loss of steric hindrance of Sec 7 binding with ARF6 leading to constitutive activation of ARF6 by Sec 7. On the other hand, a mutation at amino acid residue 359 of IQSEC2 results in constitutive hindrance of Sec 7 binding to ARF6 leading to the loss of the ability of IQSEC2 to activate ARF6. These studies provide a model for dysregulation of IQSEC2 Sec 7 activity by mutant IQSEC2 proteins. Communicated by Ramaswamy H. Sarma.

Original languageEnglish
Pages (from-to)1268-1279
Number of pages12
JournalJournal of Biomolecular Structure and Dynamics
Volume42
Issue number3
Early online date20 Apr 2023
DOIs
StatePublished - 2024

Bibliographical note

Publisher Copyright:
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Keywords

  • ADP ribosylation factor (ARF)
  • Autism
  • IQSEC2
  • Sec 7
  • calmodulin
  • epilepsy
  • guanine nucleotide exchange factor (GEF)
  • intrinsically disordered proteins (IDP)
  • molecular dynamics
  • molecular modeling

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