Lochhead, M. R., Brown, A. D., Kirlin, A. C., Chitayat, S., Munro, K., Findlay, J. E., Baillie, G. S. , LeBrun, D. P., Langelaan, D. N. and Smith, S. P. (2020) Structural insights into TAZ2 domain-mediated CBP/p300 recruitment by transactivation domain 1 of the lymphopoietic transcription factor E2A. Journal of Biological Chemistry, 27, pp. 4303-4315. (doi: 10.1074/jbc.RA119.011078) (PMID:32098872)
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Abstract
The E-protein transcription factors guide immune cell differentiation, with E12 and E47 (hereafter called E2A) being essential for B-cell specification and maturation. E2A and the oncogenic chimera E2A-PBX1 contain three transactivation domains (ADs), with AD1 and AD2 having redundant, independent, and cooperative functions in a cell-dependent manner. AD1 and AD2 both mediate their functions by binding to the KIX domain of the histone acetyltransferase paralogues CREB-binding protein (CBP) and E1A-binding protein P300 (p300). This interaction is necessary for B-cell maturation and oncogenesis by E2A-PBX1 and occurs through conserved ϕ-x-x-ϕ-ϕ motifs (with ϕ denoting a hydrophobic amino acid) in AD1 and AD2. However, disruption of this interaction via mutation of the KIX domain in CBP/p300 does not completely abrogate binding of E2A and E2APBX1. Here, we determined that E2A-AD1 and E2A-AD2 also interact with the TAZ2 domain of CBP/p300. Characterization of the TAZ2:E2AAD1(1-37) complex indicated that E2A-AD1 adopts an α-helical structure and uses its ϕ-x-x-ϕ-ϕ motif to bind TAZ2. While this region overlapped with the KIX recognition region, key KIX-interacting E2A-AD1 residues were exposed, suggesting that E2A-AD1 could simultaneously bind both the KIX and TAZ2 domains. However, we did not detect a ternary complex involving E2A-AD1, KIX, and TAZ2 and found that E2A containing both intact AD1 and AD2 is required to bind to CBP/p300. Our findings highlight the structural plasticity and promiscuity of E2A-AD1 and suggest that E2A binds both the TAZ2 and KIX domains of CBP/p300 through AD1 and AD2.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Findlay, Mrs Jane and Baillie, Professor George |
Authors: | Lochhead, M. R., Brown, A. D., Kirlin, A. C., Chitayat, S., Munro, K., Findlay, J. E., Baillie, G. S., LeBrun, D. P., Langelaan, D. N., and Smith, S. P. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
Journal Name: | Journal of Biological Chemistry |
Publisher: | American Society for Biochemistry and Molecular Biology, Inc. |
ISSN: | 0021-9258 |
ISSN (Online): | 1083-351X |
Published Online: | 25 February 2020 |
Copyright Holders: | Copyright © 2020 The Authors |
First Published: | First published in Journal of Biological Chemistry 27:4303-4315 |
Publisher Policy: | Reproduced in accordance with the copyright policy of the publisher |
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