Integrative proteomic analysis and molecular dynamics simulations of ANKLE2 reveal mechanisms of microcephaly
- 1University of California, Davis
Abstract
ANKLE2 is a scaffolding protein with crucial roles in neuroprogenitor cell division and embryonic brain development. Pathogenic variants in ANKLE2 cause primary microcephaly, a congenital disorder characterized by impaired neurodevelopment. Nonetheless, the underlying dysfunction of ANKLE2 is not understood. Here, we define the ANKLE2 protein interaction landscape, which includes cell division proteins and novel microcephaly candidates in the APC (anaphase-promoting complex). Analysis of six pathogenic variants reveals changes in this interactome that likely result in microcephaly. Using molecular simulations, we identify the structural consequences of five pathogenic substitutions, including disruption of important helical structures. Combined, these techniques suggest loss of interaction with the PP2A (protein phosphatase 2A) complex is a common mechanism for ANKLE2 pathogenesis. Phosphoproteomics reveals widespread alterations in ANKLE2- and PP2A-dependent phosphorylation of cell division proteins. Together, our integrative proteomics and simulation approach improves the molecular understanding of ANKLE2 function and its pathogenic changes in primary microcephaly.
Related
- Integrative lipidomic and proteomic analysis reveals the mechanisms of freezing tolerance in Meloidogyne incognita eggs
- Integrative network pharmacology, machine learning, and experimental validation reveal the protective potential and potential molecular mechanisms of orientin in DSS-induced colitis
- Integrative molecular mechanisms of lodging resistance in rice (Oryza sativa L.) culms: from DELLA–OsGSK2–BZR1 signaling to cell wall engineering and QTL-based breeding
- Integrated Physiological, Transcriptomic, and Proteomic Analyses Reveal Alkali Stress Response and Tolerance Mechanisms of Rhododendron obtusum ‘Fenzhuanglou’ Seedlings
- Neurobiological mechanisms and brain network dysfunction in major depressive disorder: an integrative review
BibTeX
@misc{fishburn2026integrative,
title = {{Integrative proteomic analysis and molecular dynamics simulations of ANKLE2 reveal mechanisms of microcephaly}},
author = {A. T. Fishburn and V. Peddamallu and N. J. Lopez and I. M. Bilkic and I. J. Hixson and E. Mambou and H. Pan and B. Bonaventure and C. J. Florio and C. L. S. Skawinski and M. Lopez Ramos and P. R. Bandivadekar and S. S. Becker and B. L. Gidugu and J. L. A. Fishburn and A. P. Gudinas and J. H. Barlow and D. J. Mai and S.-H. Ahn and J. R. Johnson and N. L. Link and P. S. Shah},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.755110},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.755110v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Integrative proteomic analysis and molecular dynamics simulations of ANKLE2 reveal mechanisms of microcephaly
AU - A. T. Fishburn
AU - V. Peddamallu
AU - N. J. Lopez
AU - I. M. Bilkic
AU - I. J. Hixson
AU - E. Mambou
AU - H. Pan
AU - B. Bonaventure
AU - C. J. Florio
AU - C. L. S. Skawinski
AU - M. Lopez Ramos
AU - P. R. Bandivadekar
AU - S. S. Becker
AU - B. L. Gidugu
AU - J. L. A. Fishburn
AU - A. P. Gudinas
AU - J. H. Barlow
AU - D. J. Mai
AU - S.-H. Ahn
AU - J. R. Johnson
AU - N. L. Link
AU - P. S. Shah
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.755110
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.755110v1
AB - ANKLE2 is a scaffolding protein with crucial roles in neuroprogenitor cell division and embryonic brain development. Pathogenic variants in ANKLE2 cause primary microcephaly, a congenital disorder characterized by impaired neurodevelopment. Nonetheless, the underlying dysfunction of ANKLE2 is not understood. Here, we define the ANKLE2 protein interaction landscape, which includes cell division proteins and novel microcephaly candidates in the APC (anaphase-promoting complex). Analysis of six pathogenic variants reveals changes in this interactome that likely result in microcephaly. Using molecular simulations, we identify the structural consequences of five pathogenic substitutions, including disruption of important helical structures. Combined, these techniques suggest loss of interaction with the PP2A (protein phosphatase 2A) complex is a common mechanism for ANKLE2 pathogenesis. Phosphoproteomics reveals widespread alterations in ANKLE2- and PP2A-dependent phosphorylation of cell division proteins. Together, our integrative proteomics and simulation approach improves the molecular understanding of ANKLE2 function and its pathogenic changes in primary microcephaly.
ER -