Role of POGLUT2 and POGLUT3 in regulating microfibril structure and function
POGLUT2和POGLUT3在调节微纤维结构和功能中的作用
基本信息
- 批准号:10636927
- 负责人:
- 金额:$ 68.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAffinityAlanineAmino AcidsAortaBindingBinding ProteinsBinding SitesBiological AssayBirthBone GrowthCalciumCalcium BindingCell Differentiation processCellsCessation of lifeConsensusConsensus SequenceCysteineDataDatabasesDefectDepositionDermalDevelopmentDiseaseDissectionElastic TissueElasticityElastinElectron MicroscopyEndoplasmic ReticulumEnsureEnzymesEpidermal Growth FactorExtracellular MatrixEyeFBN1FibroblastsGeneticGlucoseGlucosyltransferasesHeartHistologicHomeostasisHumanImpairmentIn VitroKnock-outKnockout MiceLabelLigand BindingLigandsLinkLocationLungMarfan SyndromeMediatingMethodsMicrofibrilsModificationMolecularMusMutateMutationN-terminalPatientsPeptide HydrolasesPerinatalPerinatal mortality demographicsPhenotypePlayProtein SecretionProteinsRecombinantsRoleSerineSignal TransductionSiteStructural ProteinStructural defectStructureSurvivorsSyndactylyTensile StrengthTestingTissuesTransforming Growth Factor betaautosomefibrillinfibrillin-2glycoproteomicsglycosylationin vitro Assayin vivolung developmentmouse modelmutantnotch proteinnovelprotein functionpulmonary functionresponsescaffoldtrafficking
项目摘要
Protein O-glucosyltransferases 2 and 3 (POGLUT2 and POGLUT3) add an O-linked glucose to a serine
residue in Epidermal Growth factor-like (EGF) repeats containing the putative consensus sequence
C3xNTxGS(Y/F)xC4, where C3 and C4 are the third and fourth conserved cysteine in the EGF repeat. Database
searches reveal that the fibrillins (FBNs) and Latent TGFβ Binding Proteins (LTBPs) have numerous EGF
repeats with the consensus, while other proteins only have one or two. FBN1 and FBN2 are the major
structural proteins in the 10-12 nm microfibrils in extracellular matrix, where they serve as the scaffold for
elastin in elastic tissues, providing elasticity and recoil essential for function of tissues such as lung. Microfibrils
also bind a number of other molecules, including LTBPs, that regulate tissue homeostasis. Mutations in FBN1
cause Marfan Syndrome (MFS) that can result in aortic aneurism/dissection and also cause lung, bone-growth,
and eye defects. Elimination of Fbn1, Ltbp1, or Ltbp4 in mice results in perinatal lethality, recapitulating several
of the phenotypes seen in MFS patients. Nothing is known about the impact of EGF O-glucosylation on
FBN or LTBP function. Using our glycoproteomic mass spectral methods, we demonstrated that 27 of the 47
EGF repeats in FBN1 immunopurified from human dermal fibroblast cultures are modified with O-glucose.
Similar levels of O-glucose were found in recombinant FBN2, LTPB1, and LTBP4 expressed in HEK293T cells.
Secretion of an N-terminal fragment (EGF1-26) of FBN1 was significantly reduced when POGLUT2 and
POGLUT3 were knocked out in HEK293T cells, suggesting that modification by these enzymes, both localized
in the endoplasmic reticulum, are required for efficient folding and secretion of these substrates. The
importance of this O-glucose modification is underscored by our recent observation that the majority of our
Poglut2/Poglut3 double knockout (DKO) mice die perinatally. Survivors have abnormalities similar to Fbn and
Ltbp KOs including lung defects, small size, and syndactyly. Based on these observations, we hypothesize
that O-glucosylation of FBNs and LTPBs is essential for a functional microfibril network. We predict
that loss of O-glucosylation will reduce secretion of these proteins and/or disrupt binding to microfibril
associated proteins, leading to structural and/or signaling defects in tissues. We will test this hypothesis
in three Aims. Aim 1 addresses how loss of O-glucose affects POGLUT2/3 substrate proteins using cell-based
secretion assays, ultrastructural analysis of microfibrils, and analysis of FBN1-ligand interactions. Aim 2 tests
whether conserved amino acids in the putative POGLUT2/3 consensus are required for O-glucosylation, and
whether MFS mutations in these conserved residues mediate their effects on FBN1 by loss of O-glucose. Aim
3 examines whether loss of POGLUT2/3 impairs the microfibril network in developing lungs using mouse
models, histological approaches, and genetic interaction studies. Combined, these aims will provide molecular
mechanisms to explain how O-glucose affects the structure and function of the microfibril network.
蛋白质o -葡萄糖基转移酶2和3 (POGLUT2和POGLUT3)将o -连接的葡萄糖添加到丝氨酸上
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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BERNADETTE C HOLDENER其他文献
BERNADETTE C HOLDENER的其他文献
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{{ truncateString('BERNADETTE C HOLDENER', 18)}}的其他基金
Role of Beta3-Glucosyltransferase in a non-canonical quality control pathway
Beta3-葡萄糖基转移酶在非规范质量控制途径中的作用
- 批准号:
10427381 - 财政年份:2018
- 资助金额:
$ 68.74万 - 项目类别:
Role of Beta3-Glucosyltransferase in a non-canonical quality control pathway
Beta3-葡萄糖基转移酶在非规范质量控制途径中的作用
- 批准号:
10221012 - 财政年份:2018
- 资助金额:
$ 68.74万 - 项目类别:
Role of Beta3-Glucosyltransferase in a non-canonical quality control pathway
Beta3-葡萄糖基转移酶在非规范质量控制途径中的作用
- 批准号:
9579777 - 财政年份:2018
- 资助金额:
$ 68.74万 - 项目类别:
Biochemical and genetic analysis of mesd function
med功能的生化和遗传分析
- 批准号:
6921930 - 财政年份:1997
- 资助金额:
$ 68.74万 - 项目类别:
Biochemical and genetic analysis of mesd function
med功能的生化和遗传分析
- 批准号:
7194947 - 财政年份:1997
- 资助金额:
$ 68.74万 - 项目类别:
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