| Title: |
Structural analysis of HERC2/UBE3A and HERC2/DOCK10 complexes provides new insights into the molecular basis of Angelman, Angelman-like and Dup15q Syndromes |
| Authors: |
Demenge, Auguste; Lim, Jiawen; Roc, Arpoudamarie; Zambo, Boglarka; Gogl, Gergo; Cousido-Siah, Alexandra; Mcewen, Alastair, G; Bonhoure, Anna; Kostmann, Camille; Fagotto-Kaufmann, Christine; Eberling, Pascal; Osz-Papai, Judit; Podjarny, Alberto; Howard, Eduardo; Golzio, Christelle; Debant, Anne; Schmidt, Susanne; Travé, Gilles |
| Contributors: |
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC); Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Centre de recherche en Biologie cellulaire de Montpellier (CRBM); Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM); ANR-18-CE92-0017,UBE3A,Ubiquitine-ligase E6AP: Analyse structurale et modulation par de petites molécules.(2018); ANR-22-CE44-0018,Full-PDZ-PBM-HPVE6,Cartographie complete des affinités de l'interactome PDZ-PBM humain et relation interactome-phenotype de l' oncoprotéine E6 du virus HPV(2022); ANR-22-CE11-0026,HERC2-DOCKD-Modul,Interaction de l'Ub-ligase HERC2 avec les RhoGEFs DOCKD: études structure-interactome-fonction et implication dans la synaptogénèse et des syndromes du neurodéveloppement.(2022); ANR-19-CE16-0004,TRIOTISM,Role du RhoGEF TRIO dans les maladies neurodévelopementales(2019) |
| Source: |
https://hal.science/hal-05343131 ; 2025. |
| Publisher Information: |
CCSD |
| Publication Year: |
2025 |
| Collection: |
Université de Montpellier: HAL |
| Subject Terms: |
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry; Molecular Biology/Structural Biology [q-bio.BM]; [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis; [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| Description: |
International audience ; UBE3A and HERC2 are two mutually interacting HECT E3 Ubiquitin ligases whose genes are altered in 15q11.2-13.1 Duplication (Dup15q) Syndrome, Angelman Syndrome (AS) and other phenotypically-related mental retardation syndromes. Using quantitative binding assays, X-ray crystallography and sequence conservation analysis, we show that the HERC2/UBE3A complex occurs in probably most animals with a central nervous system, via a conserved interface involving the RLD2 domain of HERC2 and a "DxDKDxD" motif of UBE3A. We found that HERC2 also recognizes and binds to similar DxDKDxD motifs within a handful of other proteins relevant to brain development (DOCK10, PCM1, USP35, BAZ2B, ARID4A, ARIP4, RERE and MYT1). We further investigated the interaction of HERC2 with DOCK10, a RAC1and CDC42-GEF protein that regulates dendritic spine morphogenesis in hippocampal neurons. Both disruption of the HERC2-binding motif in DOCK10 and knockdown of HERC2 affected the GEF activity of DOCK10. We also show that the DOCK10-induced dendritic spine formation is dependent on its ability to bind HERC2. Structural modeling of full-length DOCK10, free or bound to either RLD2, CDC42 or RAC1 indicates that the GEF activation of full-length DOCK10 requires a conformational change that is stimulated by binding to HERC2. Based on our data, we propose that under pathological conditions, in developing brains with an abnormal dosage of either HERC2 or its dominant partner UBE3A, increased or decreased amounts of HERC2/DOCK10 complexes could lead to altered GTPase activation. This in turn could affect dendritic spine formation and neurodevelopment. |
| Document Type: |
report |
| Language: |
English |
| Relation: |
BIORXIV: 2025.09.16.670041 |
| Availability: |
https://hal.science/hal-05343131; https://hal.science/hal-05343131v1/document; https://hal.science/hal-05343131v1/file/BIORXIV-2025-670041v1-TRAVE.pdf |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.7DFEA4CF |
| Database: |
BASE |