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Evolution of an amniote-specific mechanism for modulating ubiquitin signalling via phosphoregulation of the E2 enzyme UBE2D3

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Title: Evolution of an amniote-specific mechanism for modulating ubiquitin signalling via phosphoregulation of the E2 enzyme UBE2D3
Authors: Roman-Trufero, M
Ito, CM
Pedebos, C
Magdalou, I
Wang, Y-F
Karimi, MM
Moyon, B
Webster, Z
Di Gregorio, A
Azuara, V
Khalid, S
Speck, C
Rodriguez, T
Dillon, N
Item Type: Journal Article
Abstract: Genetic variation in the enzymes that catalyse post-translational modification of proteins is a potentially important source of phenotypic variation during evolution. Ubiquitination is one such modification that affects turnover of virtually all of the proteins in the cell in addition to roles in signalling and epigenetic regulation. UBE2D3 is a promiscuous E2 enzyme, which acts as a ubiquitin donor for E3 ligases that catalyse ubiquitination of developmentally important proteins. We have used protein sequence comparison of UBE2D3 orthologues to identify a position in the C-terminal α-helical region of UBE2D3 that is occupied by a conserved serine in amniotes and by alanine in anamniote vertebrate and invertebrate lineages. Acquisition of the serine (S138) in the common ancestor to modern amniotes created a phosphorylation site for Aurora B. Phosphorylation of S138 disrupts the structure of UBE2D3 and reduces the level of the protein in mouse ES cells (ESCs). Substitution of S138 with the anamniote alanine (S138A) increases the level of UBE2D3 in ESCs as well as being a gain of function early embryonic lethal mutation in mice. When mutant S138A ESCs were differentiated into extra-embryonic primitive endoderm (PrE), levels of the PDGFRα and FGFR1 receptor tyrosine kinases (RTKs) were reduced and PreE differentiation was compromised. Proximity ligation analysis showed increased interaction between UBE2D3 and the E3 ligase CBL and between CBL and the RTKs. Our results identify a sequence change that altered the ubiquitination landscape at the base of the amniote lineage with potential effects on amniote biology and evolution.
Issue Date: Jul-2020
Date of Acceptance: 26-Feb-2020
URI: http://hdl.handle.net/10044/1/78115
DOI: 10.1093/molbev/msaa060
ISSN: 0737-4038
Publisher: Oxford University Press (OUP)
Start Page: 1986
End Page: 2001
Journal / Book Title: Molecular Biology and Evolution
Volume: 37
Issue: 7
Copyright Statement: © 2020 The Author(s). Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/ licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Wellcome Trust
Medical Research Council (MRC)
Biotechnology and Biological Sciences Research Council (BBSRC)
Funder's Grant Number: 107903/Z/15/Z
MR/P018467/1
BB/S008284/1
Keywords: amniote
embryogenesis
evolution
mouse
ubiquitination
Evolutionary Biology
0601 Biochemistry and Cell Biology
0603 Evolutionary Biology
0604 Genetics
Publication Status: Published online
Conference Place: United States
Open Access location: https://www.biorxiv.org/content/10.1101/750505v2
Online Publication Date: 2020-03-12
Appears in Collections:Department of Metabolism, Digestion and Reproduction
National Heart and Lung Institute
Institute of Clinical Sciences
Faculty of Medicine