Structure analyses reveal a regulated oligomerization mechanism of the PlexinD1/GIPC/myosin VI complex

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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

The following data sets were generated

1. Shang G
2. Zhang X
(2017) Structure of apo-PlexinD1
Publicly available at the RCSB Protein Data Bank (accession no: 5V6R).

http://www.rcsb.org/pdb/explore/explore.do?structureId=5V6R
1. Shang G
2. Zhang X
(2017) Structure of apo-GIPC1
Publicly available at the RCSB Protein Data Bank (accession no: 5V6B).

http://www.rcsb.org/pdb/explore/explore.do?structureId=5V6B
1. Shang G
2. Zhang X
(2017) Structure of the PlexinD1/GIPC1 complex
Publicly available at the RCSB Protein Data Bank (accession no: 5V6T).

http://www.rcsb.org/pdb/explore/explore.do?structureId=5V6T
1. Shang G
2. Zhang X
(2017) Structure of the GIPC1-GH2/Myosin VI-HCBD complex
Publicly available at the RCSB Protein Data Bank (accession no: 5V6E).

http://www.rcsb.org/pdb/explore/explore.do?structureId=5V6E
1. Shang G
2. Zhang X
(2017) Structure of the GIPC2-GH2/Myosin VI-HCBD complex
Publicly available at the RCSB Protein Data Bank (accession no: 5V6H).

http://www.rcsb.org/pdb/explore/explore.do?structureId=5V6H

Article and author information

Author details

Guijun Shang

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Chad A Brautigam

Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Rui Chen

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Defen Lu

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Jesús Torres-Vázquez

Department of Cell Biology, New York University Langone Medical Center, New York, United States

Competing interests
The authors declare that no competing interests exist.
Xuewu Zhang

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States

For correspondence
xuewu.zhang@utsouthwestern.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3634-6711

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.

Copyright

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.