Human TRMT112-Methyltransferase Network Consists of Seven Partners Interacting with a Common Co-Factor

Methylation is an essential epigenetic modification mainly catalysed by S-Adenosyl methionine-dependent methyltransferases (MTases). Several MTases require a cofactor for their metabolic stability and enzymatic activity. TRMT112 is a small evolutionary conserved protein that acts as a co-factor and activator for different MTases involved in rRNA, tRNA and protein methylation. Using a SILAC screen, we pulled down seven methyltransferases—N6AMT1, WBSCR22, METTL5, ALKBH8, THUMPD2, THUMPD3 and TRMT11—as interaction partners of TRMT112. We showed that TRMT112 stabilises all seven MTases in cells. TRMT112 and MTases exhibit a strong mutual feedback loop when expressed together in cells. TRMT112 interacts with its partners in a similar way; however, single amino acid mutations on the surface of TRMT112 reveal several differences as well. In summary, mammalian TRMT112 can be considered as a central “hub” protein that regulates the activity of at least seven methyltransferases.

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Genetic Variation and Evolution of the 2019 Novel Coronavirus

Public Health Genomics ◽

10.1159/000513530 ◽

2021 ◽

pp. 1-13

Author(s):

Salvatore Dimonte ◽

Muhammed Babakir-Mina ◽

Taib Hama-Soor ◽

Salar Ali

Keyword(s):

Amino Acid ◽

Receptor Binding ◽

Rapid Evolution ◽

Single Amino Acid ◽

Angiotensin Converting Enzyme 2 ◽

New Type ◽

Amino Acid Mutations ◽

Host Infection ◽

Human Coronaviruses ◽

Novel Coronavirus

Introduction: SARS-CoV-2 is a new type of coronavirus causing a pandemic severe acute respiratory syndrome (SARS-2). Coronaviruses are very diverting genetically and mutate so often periodically. The natural selection of viral mutations may cause host infection selectivity and infectivity. Methods: This study was aimed to indicate the diversity between human and animal coronaviruses through finding the rate of mutation in each of the spike, nucleocapsid, envelope, and membrane proteins. Results: The mutation rate is abundant in all 4 structural proteins. The most number of statistically significant amino acid mutations were found in spike receptor-binding domain (RBD) which may be because it is responsible for a corresponding receptor binding in a broad range of hosts and host selectivity to infect. Among 17 previously known amino acids which are important for binding of spike to angiotensin-converting enzyme 2 (ACE2) receptor, all of them are conservative among human coronaviruses, but only 3 of them significantly are mutated in animal coronaviruses. A single amino acid aspartate-454, that causes dissociation of the RBD of the spike and ACE2, and F486 which gives the strength of binding with ACE2 remain intact in all coronaviruses. Discussion/Conclusion: Observations of this study provided evidence of the genetic diversity and rapid evolution of SARS-CoV-2 as well as other human and animal coronaviruses.

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Structural assessment of single amino acid mutations: application to TP53 function

Human Mutation ◽

10.1002/humu.20379 ◽

2006 ◽

Vol 27 (9) ◽

pp. 926-937 ◽

Cited By ~ 11

Author(s):

Yum L. Yip ◽

Vincent Zoete ◽

Holger Scheib ◽

Olivier Michielin

Keyword(s):

Amino Acid ◽

Single Amino Acid ◽

Structural Assessment ◽

Amino Acid Mutations

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Mutations in Plasmodium falciparumCytochrome b That Are Associated with Atovaquone Resistance Are Located at a Putative Drug-Binding Site

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.8.2100-2108.2000 ◽

2000 ◽

Vol 44 (8) ◽

pp. 2100-2108 ◽

Cited By ~ 232

Author(s):

Michael Korsinczky ◽

Nanhua Chen ◽

Barbara Kotecka ◽

Allan Saul ◽

Karl Rieckmann ◽

...

Keyword(s):

Amino Acid ◽

Binding Site ◽

Point Mutations ◽

Drug Binding ◽

Single Amino Acid ◽

Malaria Parasites ◽

Drug Binding Site ◽

Sole Agent ◽

Amino Acid Mutations

ABSTRACT Atovaquone is the major active component of the new antimalarial drug Malarone. Considerable evidence suggests that malaria parasites become resistant to atovaquone quickly if atovaquone is used as a sole agent. The mechanism by which the parasite develops resistance to atovaquone is not yet fully understood. Atovaquone has been shown to inhibit the cytochrome bc 1 (CYTbc 1) complex of the electron transport chain of malaria parasites. Here we report point mutations in Plasmodium falciparum CYT b that are associated with atovaquone resistance. Single or double amino acid mutations were detected from parasites that originated from a cloned line and survived various concentrations of atovaquone in vitro. A single amino acid mutation was detected in parasites isolated from a recrudescent patient following atovaquone treatment. These mutations are associated with a 25- to 9,354-fold range reduction in parasite susceptibility to atovaquone. Molecular modeling showed that amino acid mutations associated with atovaquone resistance are clustered around a putative atovaquone-binding site. Mutations in these positions are consistent with a reduced binding affinity of atovaquone for malaria parasite CYTb.

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Sequence specificity analysis of the SETD2 protein lysine methyltransferase and discovery of a SETD2 super-substrate

Communications Biology ◽

10.1038/s42003-020-01223-6 ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 1

Author(s):

Maren Kirstin Schuhmacher ◽

Serap Beldar ◽

Mina S. Khella ◽

Alexander Bröhm ◽

Jan Ludwig ◽

...

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Histone H3 ◽

Protein Methylation ◽

Sequence Specificity ◽

Sequence Design ◽

Substrate Peptide ◽

Lysine Methyltransferase ◽

In Cells

AbstractSETD2 catalyzes methylation at lysine 36 of histone H3 and it has many disease connections. We investigated the substrate sequence specificity of SETD2 and identified nine additional peptide and one protein (FBN1) substrates. Our data showed that SETD2 strongly prefers amino acids different from those in the H3K36 sequence at several positions of its specificity profile. Based on this, we designed an optimized super-substrate containing four amino acid exchanges and show by quantitative methylation assays with SETD2 that the super-substrate peptide is methylated about 290-fold more efficiently than the H3K36 peptide. Protein methylation studies confirmed very strong SETD2 methylation of the super-substrate in vitro and in cells. We solved the structure of SETD2 with bound super-substrate peptide containing a target lysine to methionine mutation, which revealed better interactions involving three of the substituted residues. Our data illustrate that substrate sequence design can strongly increase the activity of protein lysine methyltransferases.

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Single amino acid mutations ofMedicagoglycosyltransferase UGT85H2 enhance activity and impart reversibility

FEBS Letters ◽

10.1016/j.febslet.2009.05.046 ◽

2009 ◽

Vol 583 (12) ◽

pp. 2131-2135 ◽

Cited By ~ 30

Author(s):

Luzia V. Modolo ◽

Luis L. Escamilla-Treviño ◽

Richard A. Dixon ◽

Xiaoqiang Wang

Keyword(s):

Amino Acid ◽

Single Amino Acid ◽

Amino Acid Mutations ◽

Enhance Activity

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Functional analysis of single amino-acid mutations in the thrombopoietin-receptor Mpl underlying congenital amegakaryocytic thrombocytopenia

British Journal of Haematology ◽

10.1111/j.1365-2141.2008.07139.x ◽

2008 ◽

Vol 141 (6) ◽

pp. 808-813 ◽

Cited By ~ 14

Author(s):

Marloes R. Tijssen ◽

Franca di Summa ◽

Sonja van den Oudenrijn ◽

Jaap Jan Zwaginga ◽

C. Ellen van der Schoot ◽

...

Keyword(s):

Functional Analysis ◽

Amino Acid ◽

Single Amino Acid ◽

Thrombopoietin Receptor ◽

Amino Acid Mutations

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A Single Amino Acid Mutation in the Drosophila Myosin SH1 Domain Severely Affects Muscle Function, Myofibril Structure, Myosin Enzymatic Activity, and Actin Sliding Velocity

Biophysical Journal ◽

10.1016/j.bpj.2009.12.774 ◽

2010 ◽

Vol 98 (3) ◽

pp. 144a

Author(s):

Yang Wang ◽

William A. Kronert ◽

Girish C. Melkani ◽

Anju Melkani ◽

Sanford I. Bernstein

Keyword(s):

Amino Acid ◽

Enzymatic Activity ◽

Muscle Function ◽

Single Amino Acid ◽

Sliding Velocity ◽

Amino Acid Mutation ◽

Single Amino Acid Mutation

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Ten emerging SARS-CoV-2 spike variants exhibit variable infectivity, animal tropism, and antibody neutralization

Communications Biology ◽

10.1038/s42003-021-02728-4 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Li Zhang ◽

Zhimin Cui ◽

Qianqian Li ◽

Bo Wang ◽

Yuanling Yu ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Amino Acid ◽

Receptor Binding ◽

Immune Escape ◽

Cathepsin L ◽

Single Amino Acid ◽

Receptor Binding Domain ◽

Therapeutic Antibodies ◽

Amino Acid Mutations ◽

Better Than

AbstractEmerging mutations in SARS-CoV-2 cause several waves of COVID-19 pandemic. Here we investigate the infectivity and antigenicity of ten emerging SARS-CoV-2 variants—B.1.1.298, B.1.1.7(Alpha), B.1.351(Beta), P.1(Gamma), P.2(Zeta), B.1.429(Epsilon), B.1.525(Eta), B.1.526-1(Iota), B.1.526-2(Iota), B.1.1.318—and seven corresponding single amino acid mutations in the receptor-binding domain using SARS-CoV-2 pseudovirus. The results indicate that the pseudovirus of most of the SARS-CoV-2 variants (except B.1.1.298) display slightly increased infectivity in human and monkey cell lines, especially B.1.351, B.1.525 and B.1.526 in Calu-3 cells. The K417N/T, N501Y, or E484K-carrying variants exhibit significantly increased abilities to infect mouse ACE2-overexpressing cells. The activities of furin, TMPRSS2, and cathepsin L are increased against most of the variants. RBD amino acid mutations comprising K417T/N, L452R, Y453F, S477N, E484K, and N501Y cause significant immune escape from 11 of 13 monoclonal antibodies. However, the resistance to neutralization by convalescent serum or vaccines elicited serum is mainly caused by the E484K mutation. The convalescent serum from B.1.1.7- and B.1.351-infected patients neutralized the variants themselves better than other SARS-CoV-2 variants. Our study provides insights regarding therapeutic antibodies and vaccines, and highlights the importance of E484K mutation.

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Globally Defining the Effects of Amino Acid Mutations across a Picornavirus Capsid

Proceedings ◽

10.3390/proceedings2020050111 ◽

2020 ◽

Vol 50 (1) ◽

pp. 111

Author(s):

Florian Mattenberger ◽

Ron Geller

Keyword(s):

Amino Acid ◽

Rna Viruses ◽

Large Fraction ◽

Protein Structures ◽

Single Amino Acid ◽

Relative Fitness ◽

Mutation Rates ◽

Phenotypic Data ◽

Synonymous Mutations ◽

Amino Acid Mutations

RNA viruses are characterized by their extreme mutation rates, which play key roles in their biology and give them the ability to rapidly adapt to new environments. However, non-synonymous mutations tend to be largely deleterious to protein function, raising the question of how the proteins of RNA viruses maintain functionality in the face of high mutation rates. This is of particular relevance to the capsids of non-enveloped RNA viruses, which form highly complex protein structures that assemble from numerous subunits, interact with cellular host factors to mediate entry and uncoating, and are under strong immune selection. To better understand how viral capsids accommodate mutations, we generated viral populations harboring a large fraction of all possible single amino acid mutations in a picornavirus capsid. We then used high-fidelity next-generation sequencing to derive the relative fitness of these mutations compared to the wildtype sequence. Combining our results with available structural, genetic, and phenotypic data, we are able to provide a comprehensive understanding of the ability of a viral capsid to accommodate mutations.

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