Competition between two high- and low-affinity protein-binding sites in myosin VI controls its cellular function.

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 motif and a low-affinity motif within myosin VI. These two motifs allow 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.

• Authors: Natalia Fili, Yukti Hari-Gupta, Bjork Aston, Ália Dos Santos, Rosemarie E Gough, Bana Alamad, Lin Wang, Marisa L Martin-Fernandez, Christopher P Toseland
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 295 Issue 2 Pg. 337-347 (01 10 2020) ISSN: 1083-351X [Electronic] United States
• PMID: 31744880 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Fili et al.

Chemical References

• Adaptor Proteins, Signal Transducing
• Apoptosis Regulatory Proteins
• DAB2 protein, human
• myosin VI
• Myosin Heavy Chains

Topics

• Adaptor Proteins, Signal Transducing (analysis, metabolism)
• Apoptosis Regulatory Proteins (analysis, metabolism)
• Binding Sites
• Cell Nucleus (metabolism)
• HeLa Cells
• Humans
• MCF-7 Cells
• Myosin Heavy Chains (analysis, metabolism)
• Protein Binding
• Protein Interaction Maps
• Protein Multimerization