NMR structure note: human esophageal cancer-related gene 2

Feng, Yingang; Geng, Yong; Zhou, Tao; Wang, Jinfeng

doi:10.1007/s10858-012-9622-9

Cited by 5 publications

(4 citation statements)

References 18 publications

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“…Recently, the NMR structure of CmPI-II, an inhibitor of trypsin, human neutrophil elastase, and subtilisin A, was elucidated and the complex with the latter modeled (Cabrera-Munoz et al, 2019). Similar to the recent structural study on SPINK6 (Jung et al, 2016) from the serine protease inhibitors of Kazal-type family (SPINK) (Feng et al, 2012), the authors describe a flexible N-terminal region and attribute the P2 site potential for alternative interactions in the complex formation.…”

Section: Kazal- Kunitz- and Defensin-type Foldsmentioning

confidence: 84%

Cysteines and Disulfide Bonds as Structure-Forming Units: Insights From Different Domains of Life and the Potential for Characterization by NMR

et al. 2020

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Disulfide bridges establish a fundamental element in the molecular architecture of proteins and peptides which are involved e.g., in basic biological processes or acting as toxins. NMR spectroscopy is one method to characterize the structure of bioactive compounds including cystine-containing molecules. Although the disulfide bridge itself is invisible in NMR, constraints obtained via the neighboring NMR-active nuclei allow to define the underlying conformation and thereby to resolve their functional background. In this mini-review we present shortly the impact of cysteine and disulfide bonds in the proteasome from different domains of life and give a condensed overview of recent NMR applications for the characterization of disulfide-bond containing biomolecules including advantages and limitations of the different approaches.

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Section: Kazal- Kunitz- and Defensin-type Foldsmentioning

confidence: 84%

Cysteines and Disulfide Bonds as Structure-Forming Units: Insights From Different Domains of Life and the Potential for Characterization by NMR

et al. 2020

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“…The structures of two other members of the SPINK family have been previously solved – i.e. SPINK2 [25] and SPINK7 [26]. Fig.…”

Section: Resultsmentioning

confidence: 99%

The solution structure of the kallikrein-related peptidases inhibitor SPINK6

Jung

Fischer

Spudy

et al. 2016

Biochemical and Biophysical Research Communications

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Kallikrein-related peptidases (KLKs) are crucial for epidermal barrier function and are involved in the proteolytic regulation of the desquamation process. Elevated KLK levels were reported in atopic dermatitis. In skin, the proteolytic activity of KLKs is regulated by specific inhibitors of the serine protease inhibitor of Kazal-type (SPINK) family. SPINK6 was shown to be expressed in human stratum corneum and is able to inhibit several KLKs such as KLK4, -5, -12, -13 and -14. In order to understand the structural traits of the specific inhibition we solved the structure of SPINK6 in solution by NMR-spectroscopy and studied its interaction with KLKs. Thereby, beside the conserved binding mode, we identified an alternate binding mode which has so far not been observed for SPINK inhibitors.

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“…ECRG2 protein harbors an N-terminal signal peptide (a.a. 1–20), a central linker region, and a C-terminal conserved Kazal-type serine peptidase inhibitor domain (a.a. 31–85) ( Figure 1 A) that is shared by all serine protease inhibitor Kazal (SPINK) family proteins (discussed below) [ 10 , 14 ]. Structurally, ECRG2 is composed of two alpha helices and three beta sheets ( Figure 1 B) [ 14 ]; the Kazal-type domain of ECRG2 contains six conserved cysteine residues (Cys32, Cys45, Cys53, Cys64, Cys67, and Cys85) ( Figure 1 B), which form three intra-molecular disulfide bonds (Cys32–Cys67, Cys45–Cys64, and Cys53–Cys85) [ 10 , 14 ]. Studies have demonstrated that the correct formation of these disulfide bonds is important for protein structure and function [ 14 , 15 ].…”

Section: Identification and Molecular Characteristics Of Ecrg2mentioning

confidence: 99%

“…Structurally, ECRG2 is composed of two alpha helices and three beta sheets ( Figure 1 B) [ 14 ]; the Kazal-type domain of ECRG2 contains six conserved cysteine residues (Cys32, Cys45, Cys53, Cys64, Cys67, and Cys85) ( Figure 1 B), which form three intra-molecular disulfide bonds (Cys32–Cys67, Cys45–Cys64, and Cys53–Cys85) [ 10 , 14 ]. Studies have demonstrated that the correct formation of these disulfide bonds is important for protein structure and function [ 14 , 15 ]. ECRG2 protein has an N-terminal signal peptide sequence and is predicted to be a secreted protein ( Figure 1 A).…”

Section: Identification and Molecular Characteristics Of Ecrg2mentioning

confidence: 99%

ECRG2/SPINK7 Tumor Suppressor as Modulator of DNA Damage Response

Patel,

Sheikh,

Huang

2024

IJMS

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Esophageal Cancer-Related Gene 2 (ECRG2), also known as Serine Peptidase Inhibitor Kazal type 7 (SPINK7), is a novel tumor suppressor gene from the SPINK family of genes that exhibits anticancer potential. ECRG2 was originally identified during efforts to discover genes involved in esophageal tumorigenesis. ECRG2 was one of those genes whose expression was absent or reduced in primary human esophageal cancers. Additionally, absent or reduced ECRG2 expression was also noted in several other types of human malignancies. ECRG2 missense mutations were identified in various primary human cancers. It was reported that a cancer-derived ECRG2 mutant (valine to glutamic acid at position 30) failed to induce cell death and caspase activation triggered by DNA-damaging anticancer drugs. Furthermore, ECRG2 suppressed cancer cell proliferation in cultured cells and grafted tumors in animals and inhibited cancer cell migration/invasion and metastasis. ECRG2 also was identified as a negative regulator of Hu-antigen R (HuR), an oncogenic RNA-binding protein that is known to regulate mRNA stability and the expression of transcripts corresponding to many cancer-related genes. ECRG2 function is important also for the regulation of inflammatory responses and the maintenance of epithelial barrier integrity in the esophagus. More recently, ECRG2 was discovered as one of the newest members of the pro-apoptotic transcriptional targets of p53. Two p53-binding sites (BS-1 and BS-2) were found within the proximal region of the ECRG2 gene promoter; the treatment of DNA-damaging agents in cancer cells significantly increased p53 binding to the ECRG2 promoter and triggered a strong ECRG2 promoter induction following DNA damage. Further, the genetic depletion of ECRG2 expression significantly impeded apoptotic cell death induced by DNA damage and wild-type p53 in cancer cells. These findings suggest that the loss of ECRG2 expression, commonly observed in human cancers, could play important roles in conferring anticancer drug resistance in human cancers. Thus, ECRG2 is a novel regulator in DNA damage-induced cell death that may also be a potential target for anticancer therapeutics.

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NMR structure note: human esophageal cancer-related gene 2

Cited by 5 publications

References 18 publications

Cysteines and Disulfide Bonds as Structure-Forming Units: Insights From Different Domains of Life and the Potential for Characterization by NMR

Cysteines and Disulfide Bonds as Structure-Forming Units: Insights From Different Domains of Life and the Potential for Characterization by NMR

The solution structure of the kallikrein-related peptidases inhibitor SPINK6

ECRG2/SPINK7 Tumor Suppressor as Modulator of DNA Damage Response

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