Structure of the UNC5H2 death domain.
UNC5Hs (UNC5H1-4) are netrin 1 receptors that are involved in axonal guidance and neuronal migration. They are dependence receptors that mediate apoptosis in the absence of netrin 1. UNC5H2-induced apoptosis depends on the interaction of the death domain at the C-terminus with the DAP-kinase death domain and caspase cleavage near the transmembrane region. Here, the crystal structure of the mouse UNC5H2 death domain has been determined at 2.1 A resolution. The domain adopts a six-helix bundle fold, which is similar to those of the other members of the death-domain superfamily. The UNC5H2 death domain is a dimer in the crystal and in solution. This homodimerized structure may represent the structure of the death domain when netrin 1 binds to the UNC5H2 receptor. Homodimerization of UNC5H2 may block the access of caspase to the cleavage site. In the death-domain dimer, residues in alpha3 and the 3(10)-helix preceding alpha3 and the residues in alpha4 make significant contacts, mainly by hydrophobic and van der Waals interactions.
Handa
Noriko
N
RIKEN Genomic Sciences Center, Tsurumi, Yokohama 230-0045, Japan.
Kukimoto-Niino
Mutsuko
M
Akasaka
Ryogo
R
Murayama
Kazutaka
K
Terada
Takaho
T
Inoue
Makoto
M
Yabuki
Takashi
T
Aoki
Masaaki
M
Seki
Eiko
E
Matsuda
Takayoshi
T
Nunokawa
Emi
E
Tanaka
Akiko
A
Hayashizaki
Yoshihide
Y
Kigawa
Takanori
T
Shirouzu
Mikako
M
Yokoyama
Shigeyuki
S
D000595:Amino Acid Sequence; D000818:Animals; D019281:Dimerization; D051379:Mice; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000737:chemistry; D000075386:Netrin Receptors; D000075388:Netrin-1; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry*; D016415:Sequence Alignment; D025521:Tumor Suppressor Proteins / Q000737:chemistry
D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D000075388:Netrin-1; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C000617353:Ntn1 protein, mouse; C000617308:Unc5A protein, mouse; C000617307:Unc5b protein, mouse