Neural EP24.15- A Model for Neuropeptidase Function

神经 EP24.15- 神经肽酶功能模型

• 批准号: 7534327
• 负责人: Marc J Glucksman
• 金额: $ 33.21万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-20 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7534327
• 关键词: Affinity; Alzheimer' s Disease; Antibodies; Binding; Binding Sites; Biochemical Genetics; Biological; Biological Assay; Brain; Cancer Cell Growth; Catalysis; Cells; Cleaved cell; Collaborations; Complementary DNA; Complex; Custom; Cytosol; Development; Endocrine; Environment; Enzyme Kinetics; Enzymes; Eukaryotic Cell; Family; Gel; Goals; Growth and Development function; Hand; Immune response; Kinetics; Laboratories; Left; Ligands; Major Histocompatibility Complex; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Metalloendopeptidases; Modeling; Modification; Molecular Biology; Molecular Models; Movement; Neurodegenerative Disorders; Neuropeptides; Neurosecretory Systems; Organ; Pain; Peptides; Perception; Phage Display; Pharmaceutical Preparations; Pituitary Gland; Play; Production; Protein Binding; Protein Chemistry; Protein Isoforms; Proteins; Proteomics; Reagent; Regulation; Research Personnel; Role; Site; Site-Directed Mutagenesis; Specificity; Testing; Two-Dimensional Gel Electrophoresis; Upper arm; Viral; Work; X ray diffraction analysis; X-Ray Diffraction; design; extracellular; hormone regulation; inhibitor/antagonist; macromolecule; malignant endocrine gland neoplasm; member; molecular modeling; mutant; novel therapeutics; peptide I; programs; relating to nervous system; reproductive; small molecule; structural biology

The objective of this proposal is to investigate the substrate binding, isoforms, associated proteins, and substrate size specificity of E.C.3.4.24.15 (EP24.15), with the goal of availing design of new therapeutic drugs and small molecules, to modulate development of neuroendocrine/neurodegenerative diseases and endocrine cancer(s). EP24.15 is the prototypic member of the metalloendopeptidase family, and is widely expressed in the brain, pituitary, and reproductive organs. Extracellularly, EP24.15 cleaves and modulates neuropeptides, and thus EP24.15 plays a significant role in neuroendocrine hormone regulation, pain perception, development of neurodegenerative diseases, and prostate cancer cell growth. The goal of this proposal is to further the understanding of the functions of EP24.15, of its isoforms, and of closely related metalloendopeptidases, with the goal of understandingthe prominence of EP24.15 in neuroendocrine/neurodegenerative diseases and cancer. Therefore, this proposal will integrate biochemical, genetic, structural, and proteomic approaches to study substrate binding, isoforms, associated proteins, and substrate size specificity of EP24.15. Therefore, the specific aims are: SPECIFIC AIM 1. Elucidate functional sites conferring substrate binding and catalysis. Aim la. Determine which residues comprise the substrate (inhibitor) binding site of EP24.15. Aim Ib. Determine which residues are crucial for substrate catalysis and specificity. SPECIFIC AIM 2. Determine isoforms and protein binding partners of EP24.15 and of related enzymes. Aim 2a. Identify the extracellular and intracellular isoforms of EP24.15 and EP24.16. Aim 2b. Characterize complexes of EP24.15 with associated protein-binding partners. SPECIFIC AIM 3. Unveil new substrates and mechanism of substrate size selectivity. Aim 3a. Determine what other (neuro)peptide substrates exist for EP24.15. Aim 3b. Elucidate structural changes upon substrate binding, focusing on domain movements.

本提案的目的是研究底物结合，同种异构体，相关蛋白，

项目成果

Human membrane metallo-endopeptidase-like protein degrades both beta-amyloid 42 and beta-amyloid 40.

人膜​​金属内肽酶样蛋白可降解 β-淀粉样蛋白 42 和 β-淀粉样蛋白 40。

• DOI: 10.1016/j.neuroscience.2008.05.006
• 发表时间: 2008
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Huang,JY;Bruno,AM;Patel,CA;Huynh,AM;Philibert,KD;Glucksman,MJ;Marr,RA
• 通讯作者: Marr,RA

Novel roles of neuropeptide processing enzymes: EC3.4.24.15 in the neurome.

神经肽加工酶的新作用：神经元中的 EC3.4.24.15。

• DOI: 10.1002/jnr.10779
• 发表时间: 2003
• 期刊: Journal of neuroscience research.
• 作者: Kim,SI;Grum-Tokars,V;Swanson,TA;Cotter,EJ;Cahill,PA;Roberts,JL;Cummins,PM;Glucksman,MJ
• 通讯作者: Glucksman,MJ

Metallopeptidase inhibition potentiates bradykinin-induced hyperalgesia.

• DOI: 10.1016/j.pain.2011.02.044
• 发表时间: 2011-07
• 期刊: Pain
• 影响因子: 7.4
• 作者: Gomez R;Por ED;Berg KA;Clarke WP;Glucksman MJ;Jeske NA
• 通讯作者: Jeske NA

Interaction with calmodulin is important for the secretion of thimet oligopeptidase following stimulation.

与钙调蛋白的相互作用对于刺激后硫美特寡肽酶的分泌很重要。

• DOI: 10.1111/j.1742-4658.2009.07144.x
• 发表时间: 2009
• 期刊: The FEBS journal
• 作者: Russo,LilianC;Goñi,CamilaN;Castro,LeandroM;Asega,AmandaF;Camargo,AntonioCM;Trujillo,CleberA;Ulrich,Henning;Glucksman,MarcJ;Scavone,Cristoforo;Ferro,EmerS
• 通讯作者: Ferro,EmerS

Hydrogen bond residue positioning in the 599-611 loop of thimet oligopeptidase is required for substrate selection.

• DOI: 10.1111/j.1742-4658.2008.06685.x
• 发表时间: 2008-11
• 期刊: The FEBS journal
• 作者: Bruce LA;Sigman JA;Randall D;Rodriguez S;Song MM;Dai Y;Elmore DE;Pabon A;Glucksman MJ;Wolfson AJ
• 通讯作者: Wolfson AJ