Fili, N., Hari-Gupta, Y., Aston, B. et al. (6 more authors) (2020) Competition between two high- and low-affinity protein-binding sites in myosin VI controls its cellular function. Journal of Biological Chemistry, 295 (2). pp. 337-347. ISSN 0021-9258
Abstract
Myosin VI is involved in many cellular processes ranging from endocytosis to transcription. This multifunctional potential is achieved through alternative isoform splicing and through interactions of myosin VI with a diverse network of binding partners. However, the interplay between these two modes of regulation remains unexplored. To this end, we compared two different binding partners and their interactions with myosin VI by exploring the kinetic properties of recombinant proteins and their distribution in mammalian cells using fluorescence imaging. We found that selectivity for these binding partners is achieved through a high-affinity and a low-affinity motif within myosin VI. These two motifs allowed competition among partners for myosin VI. Exploring how this competition affects the activity of nuclear myosin VI, we demonstrate the impact of a concentration-driven interaction with the low-affinity binding partner DAB2, finding that this interaction blocks the ability of nuclear myosin VI to bind DNA and its transcriptional activity in vitro. We conclude that loss of DAB2, a tumor suppressor, may enhance myosin VI–mediated transcription. We propose that the frequent loss of specific myosin VI partner proteins during the onset of cancer leads to a higher level of nuclear myosin VI activity.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2020 ASBMB. This is an Open Access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/). |
Keywords: | myosin VI; disabled homolog 2 (DAB2); nuclear dot protein 52 (NDP52); estrogen receptor; transcription; tumor suppressor; protein-protein interaction; differentially expressed in ovarian carcinoma 2 (DOC-2); molecular motor |
Dates: |
|
Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Human Metabolism (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 27 Nov 2019 13:06 |
Last Modified: | 12 Nov 2021 08:55 |
Status: | Published |
Publisher: | Elsevier (first published by the American Society for Biochemistry & Molecular Biology) |
Refereed: | Yes |
Identification Number: | 10.1074/jbc.ra119.010142 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:153949 |