Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3
Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3
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DOI：
10.1073/pnas.0912101106
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发表时间：
2009-12-22
影响因子：
11.1
通讯作者：
Kuriyan, John
中科院分区：
文献类型：
--
作者：
Jura, Natalia;Shan, Yibing;Kuriyan, John
人表皮生长因子受体（HER）3/ErbB 3（EGF受体（EGFR）家族的成员）的激酶结构域缺少对催化至关重要的几个残基。由于EGFR家族成员的催化活性是通过不对称激酶结构域二聚体中激酶结构域之间的变构相互作用开启的，因此HER 3可能专门用作其他EGFR家族成员的激活剂。我们已经确定了HER 3激酶结构域的晶体结构，并表明它似乎被锁定为类似于EGFR和HER 4的非活性构象。虽然晶体结构显示HER 3激酶结构域结合ATP，但我们证实它是无催化活性的，但可以作为EGFR激酶结构域的激活剂。HER 3激酶结构域在晶体中形成二聚体，由激酶结构域的N-末端叶之间的疏水接触介导。该N端半段二聚体非常类似于由先前确定的晶体结构中的无活性HER 4激酶结构域形成的二聚体，并且分子动力学模拟表明HER 3和HER 4 N端半段二聚体是稳定的。HER 3和HER 4的激酶结构域在其各自的晶格中形成相似的链，其中N端半段二聚体通过C端尾部的相互交换连接在一起。这种平铺模式在HER 3和HER 4中的保守性，这是HER 3最接近的进化同源物，可能代表了HER受体的这个分支限制与EGFR家族其他成员形成活性异二聚体的配体非依赖性的一般机制。
The kinase domain of human epidermal growth factor receptor (HER) 3/ErbB3, a member of the EGF receptor (EGFR) family, lacks several residues that are critical for catalysis. Because catalytic activity in EGFR family members is switched on by an allosteric interaction between kinase domains in an asymmetric kinase domain dimer, HER3 might be specialized to serve as an activator of other EGFR family members. We have determined the crystal structure of the HER3 kinase domain and show that it appears to be locked into an inactive conformation that resembles that of EGFR and HER4. Although the crystal structure shows that the HER3 kinase domain binds ATP, we confirm that it is catalytically inactive but can serve as an activator of the EGFR kinase domain. The HER3 kinase domain forms a dimer in the crystal, mediated by hydrophobic contacts between the N-terminal lobes of the kinase domains. This N-lobe dimer closely resembles a dimer formed by inactive HER4 kinase domains in crystal structures determined previously, and molecular dynamics simulations suggest that the HER3 and HER4 N-lobe dimers are stable. The kinase domains of HER3 and HER4 form similar chains in their respective crystal lattices, in which N-lobe dimers are linked together by reciprocal exchange of C-terminal tails. The conservation of this tiling pattern in HER3 and HER4, which is the closest evolutionary homolog of HER3, might represent a general mechanism by which this branch of the HER receptors restricts ligand-independent formation of active heterodimers with other members of the EGFR family.