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

Evolution of an amniote-specific mechanism for modulating ubiquitin signalling via phosphoregulation of the E2 enzyme UBE2D3
Evolution of an amniote-specific mechanism for modulating ubiquitin signalling via phosphoregulation of the E2 enzyme UBE2D3
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.
amniote, embryogenesis, evolution, mouse, ubiquitination
1537-1719
1986-2001
Roman-Trufero, Monica
ca482e25-e9e7-4912-9a62-e5a1b7be4128
Ito, Constance M
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Pedebos, Conrado
87801080-118f-4814-8f86-3524184b0d88
Magdalou, Indiana
f98b7962-bb1c-481d-b59f-3a38bc042372
Wang, Yi-Fang
bb6f1b5c-a4e8-48d0-b213-c35c1cf6fb97
Karimi, Mohammad M
93ea28fb-c2c5-4b63-9ce2-c54d21333745
Moyon, Benjamin
4366f5c4-88d4-474d-a532-00c0a9f7efc2
Webster, Zoe
767b9598-02f7-4cd0-8f62-d222d4ccaf0b
di Gregorio, Aida
8418ee18-0bc7-4154-8fec-b012cb49fd7a
Azuara, Veronique
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Khalid, Syma
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Speck, Christian
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Rodriguez, Tristan
32abded0-6cc9-4ad0-9342-a81a648a0088
Dillon, Niall
86b3d497-dc54-40b7-acee-ecc97cc07048
Roman-Trufero, Monica
ca482e25-e9e7-4912-9a62-e5a1b7be4128
Ito, Constance M
6e721651-9e5d-412d-925e-61bf061d503c
Pedebos, Conrado
87801080-118f-4814-8f86-3524184b0d88
Magdalou, Indiana
f98b7962-bb1c-481d-b59f-3a38bc042372
Wang, Yi-Fang
bb6f1b5c-a4e8-48d0-b213-c35c1cf6fb97
Karimi, Mohammad M
93ea28fb-c2c5-4b63-9ce2-c54d21333745
Moyon, Benjamin
4366f5c4-88d4-474d-a532-00c0a9f7efc2
Webster, Zoe
767b9598-02f7-4cd0-8f62-d222d4ccaf0b
di Gregorio, Aida
8418ee18-0bc7-4154-8fec-b012cb49fd7a
Azuara, Veronique
9e141b25-75ef-4432-a06c-d0125e044286
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Speck, Christian
7693dac7-3fbc-4c41-9291-9d0e1474295e
Rodriguez, Tristan
32abded0-6cc9-4ad0-9342-a81a648a0088
Dillon, Niall
86b3d497-dc54-40b7-acee-ecc97cc07048

Roman-Trufero, Monica, Ito, Constance M, Pedebos, Conrado, Magdalou, Indiana, Wang, Yi-Fang, Karimi, Mohammad M, Moyon, Benjamin, Webster, Zoe, di Gregorio, Aida, Azuara, Veronique, Khalid, Syma, Speck, Christian, Rodriguez, Tristan and Dillon, Niall (2020) Evolution of an amniote-specific mechanism for modulating ubiquitin signalling via phosphoregulation of the E2 enzyme UBE2D3. Molecular Biology and Evolution, 37 (7), 1986-2001. (doi:10.1093/molbev/msaa060).

Record type: 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.

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Roman-Trufero et al - Accepted Manuscript
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Accepted/In Press date: 26 February 2020
e-pub ahead of print date: 7 March 2020
Keywords: amniote, embryogenesis, evolution, mouse, ubiquitination

Identifiers

Local EPrints ID: 438819
URI: http://eprints.soton.ac.uk/id/eprint/438819
ISSN: 1537-1719
PURE UUID: cee089a4-03cc-483f-9c92-d4c22e9bd9bd
ORCID for Syma Khalid: ORCID iD orcid.org/0000-0002-3694-5044

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Date deposited: 25 Mar 2020 17:30
Last modified: 26 Nov 2021 02:52

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Contributors

Author: Monica Roman-Trufero
Author: Constance M Ito
Author: Conrado Pedebos
Author: Indiana Magdalou
Author: Yi-Fang Wang
Author: Mohammad M Karimi
Author: Benjamin Moyon
Author: Zoe Webster
Author: Aida di Gregorio
Author: Veronique Azuara
Author: Syma Khalid ORCID iD
Author: Christian Speck
Author: Tristan Rodriguez
Author: Niall Dillon

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