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Sonic Hedgehog is a Calcium-regulated Zinc peptidase

Sonic Hedgehog is a Calcium-regulated Zinc peptidase
Sonic Hedgehog 是一种钙调节锌肽酶
批准号:
10308712
负责人:
HENK ROELINK
金额:
$32.94万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-02-01 至 2022-11-30

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中文摘要
翻译
Hhedgehog(HH)信号在包括哺乳动物在内的大多数动物的发育过程中发挥着核心作用,而 HH反应的异常激活与常见的癌症有关。HHS以原蛋白的形式合成 其经历产生活性N-末端结构域(HHN)和C-末端结构域的自身蛋白分解事件 (HHC)。HHN有3个结构域:N端结合HH受体补丁(PTCH),中间结构域结合HH受体补丁 钙(Ca)和第三结构域配位锌(Zn)。钙和锌结合结构域(HHN的主体)是 与一些细菌肽酶(BacHhs)高达65%的同源性,包括所有被预测为介导催化的残基 和变构调节。许多这些保守的残基在全前脑畸形中被发现突变。 先天性出生缺陷,强调它们对正常HH功能的重要性。初步研究显示, Shh(一种脊椎动物HH)固有的多肽酶活性是其释放到细胞外基质(ECM)中所必需的。 和上清液,因此用于非细胞自主信号。将Shh包含在高度保守的 多肽酶家族,跨越生命的多个领域,结合观察到的多肽酶活性 Shh的分布和信号传递需要Shh的存在,这是ShhN是一种钙离子的假设的前提。 调节锌肽酶,调节其释放,以允许非细胞自主信号传递。使用Shh突变体 除了BacHh/Shh嵌合体外,Aim1还将检查催化所需的Shh残基,底物 识别,并通过评估Shh分布和信号调节钙。目标2将确定底物 Shh介导的催化作用。Shh的两个看似合理的、非互斥的底物是Shh本身,包括 去除疏水锚定或释放ptch1-编码结构域,以及ECM蛋白多糖。在……里面 特别是,影响Shh信号和细胞外分布的硫酸乙酰肝素蛋白多糖(HSPG)是 评估为底物。Shh相关多肽酶活性的进一步鉴定及鉴定 底物将在理解Shh作为发育形态因子的作用方面具有重要的分支作用 可能提供新的靶点来抑制非细胞自主Shh信号,这是几个 癌症。
英文摘要
Hedgehog (Hh) signaling plays a central role during development in most animals, including mammals, while aberrant activation of the Hh response is associated with common cancers. Hhs are synthesized as pro-proteins that undergo an autoproteolytic event yielding the active N-terminal domain (HhN), and a C-terminal domain (HhC). HhN has 3 domains: its N-terminus binds the Hh receptor Patched (Ptch), the middle domain binds calcium (Ca) and the third domain coordinates zinc (Zn). The Ca- and Zn-binding domains (the bulk of HhN) are up to 65% identical to some bacterial peptidases (BacHhs), including all residues predicted to mediate catalysis and allosteric regulation. Many of these conserved residues are found mutated in holoprosencephaly, a congenital birth defect, emphasizing their importance for normal Hh function. Preliminary studies show that the peptidase activity intrinsic to Shh (a vertebrate Hh) is required for its release into the extracellular matrix (ECM) and the supernatant and thus for non-cell autonomous signaling. The inclusion of Shh in a highly conserved family of peptidases that spans multiple domains of life, combined with observations that the peptidase activity of Shh is required for Shh distribution and signaling form the premise of the hypothesis that ShhN is a Ca- regulated Zn-peptidase that mediates its release to allow non-cell autonomous signaling. Using Shh mutants in addition to BacHh/Shh mosaics, Aim1 will examine Shh residues that are required for catalysis, substrate recognition, and Ca regulation by assessing Shh distribution and signaling. Aim 2 will determine the substrates of Shh-mediated catalysis. Two plausible, non-mutually exclusive, substrates for Shh are Shh itself, including the removal of hydrophobic anchors or the release of the Ptch1-dinding domain, and ECM proteoglycans. In particular, heparan sulphate proteoglycans (HSPGs) that affect Shh signaling and extracellular distribution are assessed as substrates. Further characterization of the Shh-associated peptidase activity and identification of substrates will have major ramification in understanding the role of Shh as a developmental morphogen and will likely provide new targets to suppress non-cell autonomous Shh signaling that is a driving force in several cancers.
期刊论文(8)
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DOI: 10.1186/s12860-021-00359-5
发表时间: 2021-04-16
期刊: BMC molecular and cell biology
影响因子: 2.8
作者: [Jägers C, Roelink H]
通讯作者: Roelink H
Sonic Hedgehog Is a Member of the Hh/DD-Peptidase Family That Spans the Eukaryotic and Bacterial Domains of Life.
Sonic Hedgehog 是跨越真核和细菌生命领域的 Hh/DD 肽酶家族的成员。
DOI: 10.3390/jdb6020012
发表时间: 2018
期刊: Journal of developmental biology
影响因子: 2.7
作者: [Roelink,Henk]
通讯作者: Roelink,Henk
DOI: 10.1002/stem.3018
发表时间: 2019-07
期刊: Stem cells (Dayton, Ohio)
影响因子: --
作者: [Guo W, Roelink H]
通讯作者: Roelink H
DOI: 10.1371/journal.pbio.3001596
发表时间: 2022-03
期刊: PLoS biology
影响因子: 9.8
作者: []
通讯作者:
6
    The roles of Ptch1 and Disp1 in the formation of the Shh gradient
    The roles of Ptch1 and Disp1 in the formation of the Shh gradient
    The roles of Ptch1 and Disp1 in the formation of the Shh gradient
    The roles of Ptch1 and Disp1 in the formation of the Shh gradient
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