Structure analyses reveal a regulated oligomerization mechanism of the PlexinD1/GIPC/myosin VI complex
Guijun Shang,
Chad A Brautigam,
Rui Chen,
Defen Lu,
Jesús Torres-Vázquez,
Xuewu Zhang
Affiliations
Guijun Shang
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
Chad A Brautigam
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, United States
Rui Chen
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
Defen Lu
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
Jesús Torres-Vázquez
Department of Cell Biology, Skirball Institute of Biomolecular Medicine, New York, United States
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
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.
