scholarly journals GPIHBP1 C89F Neomutation and Hydrophobic C-Terminal Domain G175R Mutation in Two Pedigrees with Severe Hyperchylomicronemia

2011 ◽  
Vol 96 (10) ◽  
pp. E1675-E1679 ◽  
Author(s):  
Sybil Charrière ◽  
Noël Peretti ◽  
Sophie Bernard ◽  
Mathilde Di Filippo ◽  
Agnès Sassolas ◽  
...  
Keyword(s):  
Critical Role ◽  
Phenotypic Expression ◽  
Missense Mutations ◽  
Terminal Domain ◽  
Apoa5 Gene ◽  
Key Enzyme ◽  
History Of ◽  
Functional Consequences ◽  
Signal Peptide Polymorphism

Abstract Context: GPIHBP1 is a new endothelial binding site for lipoprotein lipase (LPL), the key enzyme for intravascular lipolysis of triglyceride-rich lipoproteins (TGRL). We have identified two new missense mutations of the GPIHBP1 gene, C89F and G175R, by systematic sequencing in a cohort of 376 hyperchylomicronemic patients without mutations on the LPL, APOC2, or APOA5 gene. Objective: Phenotypic expression and functional consequences of these two mutations were studied. Design: We performed clinical and genotypic studies of probands and their families. GPIHBP1 functional alterations were studied in CHO pgsA-745 transfected cells. Results: Probands are an adult with a homozygous G175R mutation and a child with a hemizygous C89F neomutation and a deletion of the second allele. C89F mutation was associated with a C14F signal peptide polymorphism on the same haplotype. Both patients had resistant hyperchylomicronemia, low LPL activity, and history of acute pancreatitis. In CHO pgsA-745 cells, both G175R and C14F variants reduce the expression of GPIHBP1 at the cell surface. C89F mutation is responsible for a drastic LPL-binding defect to GPIHBP1. C14F may further potentiate C89F effect. Conclusions: The emergence of hyperchylomicronemia in the generation after a neomutation further establishes a critical role for GPIHBP1 in TGRL physiopathology in humans. Our results highlight the crucial role of C65-C89 disulfide bond in LPL binding by GPIHBP1 Ly6 domain. Furthermore, we first report a mutation of the hydrophobic C-terminal domain that impairs GPIHBP1 membrane targeting.

scholarly journals Catalytic effectiveness of human aldose reductase. Critical role of C-terminal domain.

1992 ◽  
Vol 267 (29) ◽  
pp. 20965-20970
Author(s):  
K.M. Bohren ◽  
C.E. Grimshaw ◽  
K.H. Gabbay
Keyword(s):  
Aldose Reductase ◽  
Critical Role ◽  
Terminal Domain

scholarly journals Prediction of Functional Consequences of Missense Mutations in ANO4 Gene

2021 ◽  
Vol 22 (5) ◽  
pp. 2732
Author(s):  
Nadine Reichhart ◽  
Vladimir M. Milenkovic ◽  
Christian H. Wetzel ◽  
Olaf Strauß
Keyword(s):  
Transmembrane Protein ◽  
Functional Characterization ◽  
Missense Mutations ◽  
Mutant Proteins ◽  
Functional Consequences ◽  
New Perspective ◽  
The Stability ◽  
Dynamics Simulations ◽  
And Function

The anoctamin (TMEM16) family of transmembrane protein consists of ten members in vertebrates, which act as Ca2+-dependent ion channels and/or Ca2+-dependent scramblases. ANO4 which is primarily expressed in the CNS and certain endocrine glands, has been associated with various neuronal disorders. Therefore, we focused our study on prioritizing missense mutations that are assumed to alter the structure and stability of ANO4 protein. We employed a wide array of evolution and structure based in silico prediction methods to identify potentially deleterious missense mutations in the ANO4 gene. Identified pathogenic mutations were then mapped to the modeled human ANO4 structure and the effects of missense mutations were studied on the atomic level using molecular dynamics simulations. Our data show that the G80A and A500T mutations significantly alter the stability of the mutant proteins, thus providing new perspective on the role of missense mutations in ANO4 gene. Results obtained in this study may help to identify disease associated mutations which affect ANO4 protein structure and function and might facilitate future functional characterization of ANO4.

Friends of Rose Canyon

2018 ◽  
Vol 95 (3) ◽  
pp. 2-20 ◽  
Author(s):  
Andrew Wiese
Keyword(s):  
Open Space ◽  
Critical Role ◽  
First Century ◽  
Grassroots Politics ◽  
History Of ◽  
University City ◽  
Participant Observer ◽  
The Rose

Place-based activism has played a critical role in the history of urban and environmental politics in California. This article explores the continuing significance of environmental place making to grassroots politics through a case study of Friends of Rose Canyon, an environmental group in San Diego. Based in the fast-growing University City neighborhood, Friends of Rose Canyon waged a long, successful campaign between 2002 and 2018 to prevent construction of a bridge in the Rose Canyon Open Space Park in their community. Using historical and participant observer methodologies, this study reveals how twenty-first-century California urbanites claimed and created meaningful local places and mobilized effective politics around them. It illuminates the critical role of individual activists; suggests practical, replicable strategies for community mobilization; and demonstrates the significant impact of local activism at the urban and metropolitan scales.

scholarly journals CHEK2∗1100delC Mutation and Risk of Prostate Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Victoria Hale ◽  
Maren Weischer ◽  
Jong Y. Park
Keyword(s):  
Prostate Cancer ◽  
Current Knowledge ◽  
Prostate Cancer Screening ◽  
Critical Role ◽  
Prostate Cancer Risk ◽  
Conclusive Evidence ◽  
Increased Risk ◽  
History Of ◽  
Cancer Studies

Although the causes of prostate cancer are largely unknown, previous studies support the role of genetic factors in the development of prostate cancer.CHEK2plays a critical role in DNA replication by responding to double-stranded breaks. In this review, we provide an overview of the current knowledge of the role of a genetic variant, 1100delC, ofCHEK2on prostate cancer risk and discuss the implication for potential translation of this knowledge into clinical practice. Currently, twelve articles that discussedCHEK2∗1100delC and its association with prostate cancer were identified. Of the twelve prostate cancer studies, five studies had independent data to draw conclusive evidence from. The pooled results of OR and 95% CI were 1.98 (1.23–3.18) for unselected cases and 3.39 (1.78–6.47) for familial cases, indicating thatCHEK2∗1100delC mutation is associated with increased risk of prostate cancer. Screening for CHEK2∗1100delC should be considered in men with a familial history of prostate cancer.

scholarly journals The Effect of Octapeptide Repeats on Prion Folding and Misfolding

2021 ◽  
Vol 22 (4) ◽  
pp. 1800
Author(s):  
Kun-Hua Yu ◽  
Mei-Yu Huang ◽  
Yi-Ru Lee ◽  
Yu-Kie Lin ◽  
Hau-Ren Chen ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Age Of Onset ◽  
Prion Diseases ◽  
Critical Role ◽  
Threshold Effect ◽  
Central Feature ◽  
Terminal Domain ◽  
Amyloid Aggregates

Misfolding of prion protein (PrP) into amyloid aggregates is the central feature of prion diseases. PrP has an amyloidogenic C-terminal domain with three α-helices and a flexible tail in the N-terminal domain in which multiple octapeptide repeats are present in most mammals. The role of the octapeptides in prion diseases has previously been underestimated because the octapeptides are not located in the amyloidogenic domain. Correlation between the number of octapeptide repeats and age of onset suggests the critical role of octapeptide repeats in prion diseases. In this study, we have investigated four PrP variants without any octapeptides and with 1, 5 and 8 octapeptide repeats. From the comparison of the protein structure and the thermal stability of these proteins, as well as the characterization of amyloids converted from these PrP variants, we found that octapeptide repeats affect both folding and misfolding of PrP creating amyloid fibrils with distinct structures. Deletion of octapeptides forms fewer twisted fibrils and weakens the cytotoxicity. Insertion of octapeptides enhances the formation of typical silk-like fibrils but it does not increase the cytotoxicity. There might be some threshold effect and increasing the number of peptides beyond a certain limit has no further effect on the cell viability, though the reasons are unclear at this stage. Overall, the results of this study elucidate the molecular mechanism of octapeptides at the onset of prion diseases.

scholarly journals Molecular basis of the dual role of the Mlh1-Mlh3 endonuclease in MMR and in meiotic crossover formation

2021 ◽  
Vol 118 (23) ◽  
pp. e2022704118
Author(s):  
Jingqi Dai ◽  
Aurore Sanchez ◽  
Céline Adam ◽  
Lepakshi Ranjha ◽  
Giordano Reginato ◽  
...  
Keyword(s):  
Meiotic Recombination ◽  
Molecular Basis ◽  
Crystal Packing ◽  
Critical Role ◽  
Holliday Junctions ◽  
Dual Roles ◽  
Terminal Domain ◽  
C Terminus ◽  
Meiotic Crossover

In budding yeast, the MutL homolog heterodimer Mlh1-Mlh3 (MutLγ) plays a central role in the formation of meiotic crossovers. It is also involved in the repair of a subset of mismatches besides the main mismatch repair (MMR) endonuclease Mlh1-Pms1 (MutLα). The heterodimer interface and endonuclease sites of MutLγ and MutLα are located in their C-terminal domain (CTD). The molecular basis of MutLγ’s dual roles in MMR and meiosis is not known. To better understand the specificity of MutLγ, we characterized the crystal structure of Saccharomyces cerevisiae MutLγ(CTD). Although MutLγ(CTD) presents overall similarities with MutLα(CTD), it harbors some rearrangement of the surface surrounding the active site, which indicates altered substrate preference. The last amino acids of Mlh1 participate in the Mlh3 endonuclease site as previously reported for Pms1. We characterized mlh1 alleles and showed a critical role of this Mlh1 extreme C terminus both in MMR and in meiotic recombination. We showed that the MutLγ(CTD) preferentially binds Holliday junctions, contrary to MutLα(CTD). We characterized Mlh3 positions on the N-terminal domain (NTD) and CTD that could contribute to the positioning of the NTD close to the CTD in the context of the full-length MutLγ. Finally, crystal packing revealed an assembly of MutLγ(CTD) molecules in filament structures. Mutation at the corresponding interfaces reduced crossover formation, suggesting that these superstructures may contribute to the oligomer formation proposed for MutLγ. This study defines clear divergent features between the MutL homologs and identifies, at the molecular level, their specialization toward MMR or meiotic recombination functions.

The Carnegie Uaxactun Project and the Development of Maya Archaeology

1990 ◽  
Vol 1 (2) ◽  
pp. 257-276 ◽  
Author(s):  
Stephen L. Black
Keyword(s):  
Large Scale ◽  
Critical Role ◽  
Carnegie Institution ◽  
Field Methods ◽  
Maya Archaeology ◽  
History Of ◽  
Maya Area

AbstractThe Carnegie Institution of Washington's 1924–1937. Uaxactun Project, one of the first large-scale excavations in the Maya area, established the role of dirt archaeology in Maya studies. The archaeologists who worked on this pioneering project developed many field methods and approaches that remain in use today. A review of the project and of the careers of its participants shows the critical role the Carnegie Uaxactun Project has played in the history of Maya archaeology.

scholarly journals Dust formation history of galaxies: A critical role of metallicity dust mass growth by accreting materials in the interstellar medium

2013 ◽  
Vol 65 (3) ◽  
pp. 213-222 ◽  
Author(s):  
Ryosuke S. Asano ◽  
Tsutomu T. Takeuchi ◽  
Hiroyuki Hirashita ◽  
Akio K. Inoue
Keyword(s):  
Interstellar Medium ◽  
Critical Role ◽  
Dust Formation ◽  
Mass Growth ◽  
Formation History ◽  
Dust Mass ◽  
History Of

scholarly journals Critical Role of Helix 4 of HIV-1 Capsid C-terminal Domain in Interactions with Human Lysyl-tRNA Synthetase

2007 ◽  
Vol 282 (44) ◽  
pp. 32274-32279 ◽  
Author(s):  
Brandie J. Kovaleski ◽  
Robert Kennedy ◽  
Ahmad Khorchid ◽  
Lawrence Kleiman ◽  
Hiroshi Matsuo ◽  
...  
Keyword(s):  
Critical Role ◽  
Trna Synthetase ◽  
Terminal Domain ◽  
Hiv 1

A History of Bodies

2018 ◽  
pp. 237-250
Author(s):  
Annette Rodríguez
Keyword(s):  
Twentieth Century ◽  
Mexican American ◽  
Critical Role ◽  
Historical Analysis ◽  
Mexican American Women ◽  
Pedagogical Choices ◽  
History Of ◽  
Definition Of ◽  
The Continuum

This chapter explores the development of pedagogical choices and historical practice via familial and professional mentorship. Rodríguez argues for the critical role of mentorship for the development of women in the historical profession. Naming her work “a history of the gaps,” she discusses widening the definition of historical actors as well as subjects of historical analysis. As an example, the chapter points to the continuum of women acting against racist violence, documenting, analyzing, and historicizing racist violence—against previously masculinist narratives. Demonstrating a “history of the gaps,” Rodríguez’s chapter concludes with the testimonies of Mexican and Mexican American women whose X marks confirmed anti-Mexican murders at the turn of the twentieth century.

Sign in / Sign up

Export Citation Format

Share Document