泛肽化－多人探戈
Fingering protein
degradation. (Left) Interactions between c-Cbl E3 ligase, UbcH7
E2, and a protein substrate. The structure shows the variant SH2 (TKB) domain of c-Cbl E3 in blue, the c-Cbl linker sequence in
purple, c-Cbl's RING finger motif in red, the UbcH7 E2 in green, and phosphorylated ZAP-70 peptide (which mimics the binding site
for E3 in the protein substrate) in orange. The UbcH7 E2 active-site cysteine is in yellow. Zinc ions are represented as
, http://www.100md.com
blue spheres. (Right) A model depicting how RING finger E3s may
participate in ubiquitination. The E3 ligase is shown as a
continuous block in purple, red, and blue. This E3 interacts
with its protein substrate (orange) and an E2 (green). The
primary binding site for the protein substrate (for example, the
SH2 domain of c-Cbl) is shown in blue. This might be a separate
, 百拇医药
polypeptide from the RING finger in multisubunit E3 complexes. A
secondary binding site for the protein substrate may exist in
the RING finger (red). The RING finger of E3s has been defined
as a primary binding site for E2; possible secondary sites for
E2 binding are shown in purple. The E2 active-site cysteine (C)
is shown forming a thioester bond with ubiquitin (Ub). Lysine
, http://www.100md.com
residues (K) in the protein substrate and in ubiquitin are
involved in formation of a polyubiquitin chain, which can target
the substrate for degradation once it is attached.
蛋白泛肽化是行将被降解的信号，此作用在信号传导、转录调控和细胞周期过程中都有出现。泛肽化过程需要三种酶，E1，泛肽激活因子；E2，泛肽连接因子；E3，泛肽化蛋白连接酶。许多E3连接酶都有一个锌稳定的RING
finger motif，此motif与E2结合，还有一个与被降解蛋白底物结合的结构域。
c-Cbl是一个著名的RING－E3，它诱导受体酪氨酸激酶途径信号分子泛肽化降解来阻断信号通路。最近在Cell上Pavletich's group报道了c-Cbl包含RING motif 和SH2结构域的片段与一个E2－UbcH7和一个酪氨酸磷酸化肽段相结合的结构信息，这些结构信息揭示了c-Cbl家族的新特点和RING－E3与E2结合的可能情况。
, 百拇医药
在哺乳动物细胞中，c-Cbl RING－E3是EGFR、PDGFR及CSF－1 R泛肽化的限速酶。c-Cbl 活性依赖于高保守的RING finger motif 与E2结合及SH2结构域与RTK结合将其泛肽化。将包括c-Cbl oncogene RING motif中第一个Cys的17个氨基酸去除后，发现c-Cbl 促RTK泛肽化的活性丧失。
如图所示，c-Cbl－UbcH7－E2结合的结构非常紧密。令人吃惊的是Pavletich's group的工作显示，E2结合于c-Cbl RING motif与E2和HECT
结构域非常相似。与对方蛋白窄沟结合的是E2两条相同的loop。
c-Cbl－UbcH7结构显示RING的氨基末端与 的结合有关。另外，此结构还可提出有关形成多聚泛肽化的可能机制。多聚泛肽化比泛肽更易被蛋白酶识别。
, 百拇医药
关于泛肽化的过程，要研究的还有很多，如RING
finger与E2结合活性的调控，及多聚泛肽究竟怎样合成。
相关文章：
P.
S. Freemont, Curr. Biol. 10, R84-7 (2000) [Medline].
N.
Zheng et al., Cell 102, 533 (2000) [Medline]. C. A. Joazeiro et al., Science 286, 309 (1999).
G.
Levkowitz et al., Mol. Cell 4, 1029 (1999) [Medline]. M.
, http://www.100md.com
Yokouchi et al., J. Biol. Chem. 274, 31707 (1999) [Medline]. V.
Bailly et al.,, Mol. Cell. Biol. 17, 4536 (1997) [Medline].
T.
Ohta et al., Mol. Cell 3, 535 (1999) [Medline]. J.
H. Seol et al., Genes Dev. 13, 1614 (1999) [Medline].
T.
Kamura et al., Science 284, 657 (1999).
, 百拇医药
P.
Tan et al., Mol. Cell 3, 527 (1999) [Medline].
D.
Skowyra et al., Science 284, 662 (1999).
T.
Kamura et al., Genes Dev. 13, 2928 (1999) [Medline].
H.
Huang et al., J. Biol. Chem. 275, 26661 (2000) [Medline]. M.
Gmachl et al., Proc. Natl. Acad. Sci. U.S.A. 97, 8973 (2000)
[Medline]. J. D. Leverson et al., Mol.
Biol. Cell 11, 2315 (2000) [Medline]., http://www.100md.com
degradation. (Left) Interactions between c-Cbl E3 ligase, UbcH7
E2, and a protein substrate. The structure shows the variant SH2 (TKB) domain of c-Cbl E3 in blue, the c-Cbl linker sequence in
purple, c-Cbl's RING finger motif in red, the UbcH7 E2 in green, and phosphorylated ZAP-70 peptide (which mimics the binding site
for E3 in the protein substrate) in orange. The UbcH7 E2 active-site cysteine is in yellow. Zinc ions are represented as
, http://www.100md.com
blue spheres. (Right) A model depicting how RING finger E3s may
participate in ubiquitination. The E3 ligase is shown as a
continuous block in purple, red, and blue. This E3 interacts
with its protein substrate (orange) and an E2 (green). The
primary binding site for the protein substrate (for example, the
SH2 domain of c-Cbl) is shown in blue. This might be a separate
, 百拇医药
polypeptide from the RING finger in multisubunit E3 complexes. A
secondary binding site for the protein substrate may exist in
the RING finger (red). The RING finger of E3s has been defined
as a primary binding site for E2; possible secondary sites for
E2 binding are shown in purple. The E2 active-site cysteine (C)
is shown forming a thioester bond with ubiquitin (Ub). Lysine
, http://www.100md.com
residues (K) in the protein substrate and in ubiquitin are
involved in formation of a polyubiquitin chain, which can target
the substrate for degradation once it is attached.
蛋白泛肽化是行将被降解的信号，此作用在信号传导、转录调控和细胞周期过程中都有出现。泛肽化过程需要三种酶，E1，泛肽激活因子；E2，泛肽连接因子；E3，泛肽化蛋白连接酶。许多E3连接酶都有一个锌稳定的RING
finger motif，此motif与E2结合，还有一个与被降解蛋白底物结合的结构域。
c-Cbl是一个著名的RING－E3，它诱导受体酪氨酸激酶途径信号分子泛肽化降解来阻断信号通路。最近在Cell上Pavletich's group报道了c-Cbl包含RING motif 和SH2结构域的片段与一个E2－UbcH7和一个酪氨酸磷酸化肽段相结合的结构信息，这些结构信息揭示了c-Cbl家族的新特点和RING－E3与E2结合的可能情况。
, 百拇医药
在哺乳动物细胞中，c-Cbl RING－E3是EGFR、PDGFR及CSF－1 R泛肽化的限速酶。c-Cbl 活性依赖于高保守的RING finger motif 与E2结合及SH2结构域与RTK结合将其泛肽化。将包括c-Cbl oncogene RING motif中第一个Cys的17个氨基酸去除后，发现c-Cbl 促RTK泛肽化的活性丧失。
如图所示，c-Cbl－UbcH7－E2结合的结构非常紧密。令人吃惊的是Pavletich's group的工作显示，E2结合于c-Cbl RING motif与E2和HECT
结构域非常相似。与对方蛋白窄沟结合的是E2两条相同的loop。
c-Cbl－UbcH7结构显示RING的氨基末端与 的结合有关。另外，此结构还可提出有关形成多聚泛肽化的可能机制。多聚泛肽化比泛肽更易被蛋白酶识别。
, 百拇医药
关于泛肽化的过程，要研究的还有很多，如RING
finger与E2结合活性的调控，及多聚泛肽究竟怎样合成。
相关文章：
P.
S. Freemont, Curr. Biol. 10, R84-7 (2000) [Medline].
N.
Zheng et al., Cell 102, 533 (2000) [Medline]. C. A. Joazeiro et al., Science 286, 309 (1999).
G.
Levkowitz et al., Mol. Cell 4, 1029 (1999) [Medline]. M.
, http://www.100md.com
Yokouchi et al., J. Biol. Chem. 274, 31707 (1999) [Medline]. V.
Bailly et al.,, Mol. Cell. Biol. 17, 4536 (1997) [Medline].
T.
Ohta et al., Mol. Cell 3, 535 (1999) [Medline]. J.
H. Seol et al., Genes Dev. 13, 1614 (1999) [Medline].
T.
Kamura et al., Science 284, 657 (1999).
, 百拇医药
P.
Tan et al., Mol. Cell 3, 527 (1999) [Medline].
D.
Skowyra et al., Science 284, 662 (1999).
T.
Kamura et al., Genes Dev. 13, 2928 (1999) [Medline].
H.
Huang et al., J. Biol. Chem. 275, 26661 (2000) [Medline]. M.
Gmachl et al., Proc. Natl. Acad. Sci. U.S.A. 97, 8973 (2000)
[Medline]. J. D. Leverson et al., Mol.
Biol. Cell 11, 2315 (2000) [Medline]., http://www.100md.com