Functional Analysis of SBP2 and Selenocysteine Incorporation

SBP2 和硒代半胱氨酸掺入的功能分析

• 批准号: 9244812
• 负责人: PAUL R COPELAND
• 金额: $ 31.45万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-06 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244812
• 关键词: 3' Untranslated Regions; Address; Amino Acids; Antioxidants; Binding Proteins; Carrier Proteins; Catalysis; Cells; Clinical; Code; Codon Nucleotides; Complex; DNA Insertion Elements; Dietary Selenium; Elements; Elongation Factor; Event; Gene Proteins; Genes; Germ; Heart Diseases; Human; Hypothyroidism; IS Elements; Immune System Diseases; Internal Ribosome Entry Site; Light; Male Infertility; Messenger RNA; Molecular; Mutation; Nuclear; Oxidation-Reduction; Oxidative Stress; Plasma; Prevention; Process; Production; Proteins; Public Health; Reaction; Regulatory Element; Ribonucleoproteins; Ribosomes; Role; Selenium; Selenocysteine; Specific qualifier value; Specificity; Sperm Motility; Terminator Codon; Tertiary Protein Structure; Thyroid Hormones; Transfer RNA; Translation Process; Translations; Wheat; cancer prevention; cofactor; hormone metabolism; human disease; mRNA Stability; novel; public health relevance; reconstitution; selenoprotein

DESCRIPTION (provided by applicant): The translation elongation cycle is the central process required for the correct decoding of mRNA into protein. Despite the extremely high level of fidelity that has been observed in this reaction, there are special circumstances that redefine the coding potential of a given mRNA. The incorporation of the 21st amino acid, selenocysteine (Sec), is one example. The transformation of a UGA stop codon into a Sec codon requires the utilization of a novel translation elongation factor (eEFSec), a selenocysteine insertion sequence (SECIS) element in the 3' untranslated region of selenoprotein mRNAs, and a novel SECIS binding protein termed SBP2. These factors act in concert to alter the coding potential of specific UGA codons by specifying the insertion of the Sec-specific tRNA, Sec-tRNASec. This process is required for the production of 25 human selenoproteins, many of which form an essential line of defense against oxidative stress. The proteins are also responsible for a myriad of other functions including thyroid hormone metabolism and maintaining proper sperm motility. We have recently demonstrated that the factors known to be essential for Sec incorporation are, in fact, sufficient. These factors include a specialized elongation factor (eEFSec), a SECIS binding protein (SBP2), a specialized transfer RNA (Sec-tRNASec) and mammalian ribosomes. Although some information about which protein domains are important for Sec incorporation activity, the mechanism by which these factors allow Sec incorporation is not known. A complete understanding of this process is required for three key reasons: 1) many selenoproteins are essential; 2) mutations in the SBP2 gene cause human disease; 3) modulation of selenoprotein production has tremendous potential to maximize the beneficial antioxidant effects of selenoproteins. We propose to address three central questions in this project: What is the molecular basis for the exquisite specificity of Sec incorporation at defined UGA codons? How are cellular dynamics involved in the specificity and efficiency of Sec incorporation? How does the 3' UTR regulate the efficient and processive incorporation of 10 selenocysteine residues into the plasma selenium carrier protein selenoprotein P (SEPP1)? Successful completion of these Aims will shed significant light on the molecular mechanism of Sec incorporation, setting the stage for identifying the means by which the process can be regulated in a clinical setting.

描述（由申请人提供）：翻译延伸周期是将mRNA正确解码为蛋白质所需的核心过程。尽管在这种反应中观察到极高的保真度，但有一些特殊情况需要重新定义