Structure analyses reveal a regulated oligomerization mechanism of the PlexinD1/GIPC/myosin VI complex
- University of Texas Southwestern Medical Center, United States
- New York University Langone Medical Center, United States
Abstract
The GIPC family adaptor proteins mediate endocytosis by tethering cargo proteins to the myosin VI motor. The structural mechanisms for the GIPC/cargo and GIPC/myosin VI interactions remained unclear. PlexinD1, a transmembrane receptor that regulates neuronal and cardiovascular development, is a cargo of GIPCs. GIPC-mediated endocytic trafficking regulates PlexinD1 signaling. Here we unravel the mechanisms of the interactions among PlexinD1, GIPCs and myosin VI by a series of crystal structures of these proteins in apo or bound states. GIPC1 forms a domain-swapped dimer in an autoinhibited conformation that hinders binding of both PlexinD1 and myosin VI. PlexinD1 binding to GIPC1 releases the autoinhibition, promoting its interaction with myosin VI. GIPCs and myosin VI interact through two distinct interfaces and form an open-ended alternating array. Our data support that this alternating array underlies the oligomerization of the GIPC/Myosin VI complexes in solution and cells.
Data availability
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Structure of apo-PlexinD1Publicly available at the RCSB Protein Data Bank (accession no: 5V6R).
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Structure of apo-GIPC1Publicly available at the RCSB Protein Data Bank (accession no: 5V6B).
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Structure of the PlexinD1/GIPC1 complexPublicly available at the RCSB Protein Data Bank (accession no: 5V6T).
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Structure of the GIPC1-GH2/Myosin VI-HCBD complexPublicly available at the RCSB Protein Data Bank (accession no: 5V6E).
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Structure of the GIPC2-GH2/Myosin VI-HCBD complexPublicly available at the RCSB Protein Data Bank (accession no: 5V6H).
Article and author information
Author details
Funding
National Institutes of Health (GM088197)
- Guijun Shang
- Rui Chen
- Xuewu Zhang
Welch Foundation (I-1702)
- Guijun Shang
- Rui Chen
- Xuewu Zhang
National Institutes of Health (R01HL133687)
- Jesús Torres-Vázquez
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Suzanne R Pfeffer, Stanford University School of Medicine, United States
Version history
- Received: March 29, 2017
- Accepted: May 23, 2017
- Accepted Manuscript published: May 24, 2017 (version 1)
- Version of Record published: June 6, 2017 (version 2)
Copyright
© 2017, Shang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structure analyses reveal a regulated oligomerization mechanism of the PlexinD1/GIPC/myosin VI complex
eLife 6:e27322.
https://doi.org/10.7554/eLife.27322
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