Peptide-Binding Sites As Revealed by the Crystal Structures of the Human Hsp40 Hdj1 C-Terminal Domain in Complex with the Octapeptide from Human Hsp70
Peptide-Binding Sites As Revealed by the Crystal Structures of the Human Hsp40 Hdj1 C-Terminal Domain in Complex with the Octapeptide from Human Hsp70
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DOI：
10.1021/bi100876n
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发表时间：
2010-10-05
期刊：
影响因子：
2.9
通讯作者：
Satow, Yoshinori
中科院分区：
文献类型：
--
作者：
Suzuki, Hironori;Noguchi, Shuji;Satow, Yoshinori
热休克蛋白（Heat shock protein，Hsp）40通过与Hsp 70蛋白协同作用在细胞过程中发挥重要作用。Hsp40蛋白识别非天然多肽，将这些肽递送到Hsp70蛋白，并刺激Hsp70蛋白的ATP酶活性以促进多肽的正确折叠。我们测定了人热休克蛋白40Hdj_1的C端肽结合结构域（CTD）及其与人热休克蛋白70C端八肽（634 ′）GPTIEEVD（641 ′）复合物的晶体结构。CTD作为扭曲的马蹄形同源二聚体存在。原聚体由两个结构域I和II组成，具有相似的拓扑结构。八肽位于结构域I的两个位点1和2。在位点1，八肽与CTD形成反平行β折叠.八肽中EEVD基序的带负电荷的残基与CTD的带正电荷的Lys残基形成静电相互作用。八肽的Ile侧链适合由CTD的疏水残基形成的狭窄凹部。在位点2中，八肽还与CTD形成反平行β折叠，并且EEVD基序形成静电相互作用。八肽的Pro和Ile的侧链与CTD位点2的疏水表面区域相互作用，该疏水表面区域比位点1的凹结合区域更宽且更浅。该区域似乎能够结合比Ile侧链大的疏水侧链。这两个肽结合位点的Hdj1的作用进行了讨论。
Heat shock protein (Hsp) 40s play essential roles in cellular processes by cooperating with Hsp70 proteins. Hsp40 proteins recognize non-native polypeptides, deliver these peptides to Hsp70 proteins, and stimulate the ATPase activity of Hsp70 proteins to facilitate the correct folding of the polypeptides. We have determined the crystal structures of the C-terminal peptide-binding domain of human Hsp40 Hdj1 (CTD) and of its complex with the C-terminal octapeptide of human Hsp70, (634')GPTIEEVD(641'). CTD exists as a twisted, horseshoe-shaped homodimer. The protomer consists of two domains, I and II, with similar topologies. The octapeptides are located in two sites, 1 and 2, of domain I. In site 1, the octapeptide forms an antiparallel beta- sheet with CTD. The negatively charged residues of the EEVD motif in the octapeptide form electrostatic interactions with the positively charged Lys residues of CTD. The Ile side chain of the octapeptide fits into the narrow concave formed by the hydrophobic residues of CTD. In site 2, the octapeptide also forms art antiparallel beta-sheet with CTD, and the EEVD motif forms electrostatic interactions. The side chains of Pro and Ile of the octapeptide interact with the hydrophobic surface region of CTD site 2, which is broader and shallower than the concave binding region of site 1. This region seems to be capable of binding hydrophobic side chains that are bulkier than the Ile side chain. The roles of these two peptide-binding sites of Hdj1 are discussed.