Structure of GABARAP in two conformations: implications for GABA(A) receptor localization and tubulin binding.
GABARAP recognizes and binds the gamma2 subunit of the GABA(A) receptor, interacts with microtubules and the N-ethyl maleimide sensitive factor, and is proposed to function in GABA(A) receptor trafficking and postsynaptic localization. We have determined the crystal structure of human GABARAP at 1.6 A resolution. The structure comprises an N-terminal helical subdomain and a ubiquitin-like C-terminal domain. Structure-based mutational analysis demonstrates that the N-terminal subdomain is responsible for tubulin binding while the C-terminal domain contains the binding site for the GABA(A). A second GABARAP crystal form was determined at 1.9 A resolution and documents that GABARAP can self-associate in a head-to-tail manner. The structural details of this oligomerization reveal how GABARAP can both promote tubulin polymerization and facilitate GABA(A) receptor clustering.
Coyle
Joseph E
JE
Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Qamar
Seema
S
Rajashankar
Kanagalaghatta R
KR
Nikolov
Dimitar B
DB
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites / Q000502:physiology; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000737:chemistry*; D008870:Microtubules / Q000378:metabolism*; D008969:Molecular Sequence Data; D009433:Neural Inhibition / Q000502:physiology*; D011108:Polymers / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology*; D011963:Receptors, GABA-A / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013570:Synaptic Membranes / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D014404:Tubulin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C116741:GABARAP protein, human; D008869:Microtubule-Associated Proteins; D011108:Polymers; D011963:Receptors, GABA-A; D014404:Tubulin