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Article ; Online: The myriad targets of a T cell.

Natarajan, Aswin / Krogsgaard, Michelle

2018 Volume 36, Issue 12, Page(s) 1152–1154

Language	English
Publishing date	2018-12-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/nbt.4309
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Zs.A 2167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Adaptive convergent evolution of genome proofreading in SARS-CoV2: insights into the Eigen's paradox

Natarajan, Vivek T / Aswin, Keerthic / Ramachandran, Srinivasan

bioRxiv

Abstract: Evolutionary history of coronaviruses holds the key to understand mutational behavior and prepare for possible future outbreaks. By performing comparative genome analysis of nidovirales that contain the family of coronaviruses, we traced the origin of ... ...

Abstract	Evolutionary history of coronaviruses holds the key to understand mutational behavior and prepare for possible future outbreaks. By performing comparative genome analysis of nidovirales that contain the family of coronaviruses, we traced the origin of proofreading, surprisingly to the eukaryotic antiviral component ZNFX1. This common recent ancestor contributes two zinc finger (ZnF) motifs that are unique to viral exonuclease, segregating them from DNA proof-readers. Phylogenetic analyses indicate that following acquisition, genomes of coronaviruses retained and further fine-tuned proofreading exonuclease, whereas related families harbor substitution of key residues in ZnF1 motif concomitant to a reduction in their genome sizes. Structural modelling followed by simulation suggests the role of ZnF in RNA binding. Key ZnF residues strongly coevolve with replicase, and the helicase involved in duplex RNA unwinding. Hence, fidelity of replication in coronaviruses is a result of convergent evolution, that enables maintenance of genome stability akin to cellular proofreading systems.
Keywords	covid19
Language	English
Publishing date	2021-09-12
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.09.11.459886
Database	COVID19

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Article ; Online: Author Correction: Molecular mechanism of phosphopeptide neoantigen immunogenicity.

Nature communications

2023 Volume 14, Issue 1, Page(s) 4522

Language	English
Publishing date	2023-07-27
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-40274-1
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Article ; Online: Catch bond models may explain how force amplifies TCR signaling and antigen discrimination.

Choi, Hyun-Kyu / Cong, Peiwen / Ge, Chenghao / Natarajan, Aswin / Liu, Baoyu / Zhang, Yong / Li, Kaitao / Rushdi, Muaz Nik / Chen, Wei / Lou, Jizhong / Krogsgaard, Michelle / Zhu, Cheng

Nature communications

2023 Volume 14, Issue 1, Page(s) 2616

Abstract: The TCR integrates forces in its triggering process upon interaction with pMHC. Force elicits TCR catch-slip bonds with strong pMHCs but slip-only bonds with weak pMHCs. We develop two models and apply them to analyze 55 datasets, demonstrating the ... ...

Abstract	The TCR integrates forces in its triggering process upon interaction with pMHC. Force elicits TCR catch-slip bonds with strong pMHCs but slip-only bonds with weak pMHCs. We develop two models and apply them to analyze 55 datasets, demonstrating the models' ability to quantitatively integrate and classify a broad range of bond behaviors and biological activities. Comparing to a generic two-state model, our models can distinguish class I from class II MHCs and correlate their structural parameters with the TCR/pMHC's potency to trigger T cell activation. The models are tested by mutagenesis using an MHC and a TCR mutated to alter conformation changes. The extensive comparisons between theory and experiment provide model validation and testable hypothesis regarding specific conformational changes that control bond profiles, thereby suggesting structural mechanisms for the inner workings of the TCR mechanosensing machinery and plausible explanations of why and how force may amplify TCR signaling and antigen discrimination.
MeSH term(s)	Receptors, Antigen, T-Cell/metabolism ; Signal Transduction ; Lymphocyte Activation ; Genes, MHC Class II ; Mutagenesis ; Protein Binding
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-05-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-38267-1
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Article ; Online: Association of Somatic TET2 Mutations With Giant Cell Arteritis.

Robinette, Michelle L / Weeks, Lachelle D / Kramer, Ryan J / Agrawal, Mridul / Gibson, Christopher J / Yu, Zhi / Sekar, Aswin / Mehta, Arnav / Niroula, Abhishek / Brown, Jared T / McDermott, Gregory C / Reshef, Edith R / Lu, Jonathan E / Liou, Victor D / Chiou, Carolina A / Natarajan, Pradeep / Freitag, Suzanne K / Rao, Deepak A / Ebert, Benjamin L

Arthritis & rheumatology (Hoboken, N.J.)

2024 Volume 76, Issue 3, Page(s) 438–443

Abstract: Objective: Giant cell arteritis (GCA) is an age-related vasculitis. Prior studies have identified an association between GCA and hematologic malignancies (HMs). How the presence of somatic mutations that drive the development of HMs, or clonal ... ...

Abstract	Objective: Giant cell arteritis (GCA) is an age-related vasculitis. Prior studies have identified an association between GCA and hematologic malignancies (HMs). How the presence of somatic mutations that drive the development of HMs, or clonal hematopoiesis (CH), may influence clinical outcomes in GCA is not well understood. Methods: To examine an association between CH and GCA, we analyzed sequenced exomes of 470,960 UK Biobank (UKB) participants for the presence of CH and used multivariable Cox regression. To examine the clinical phenotype of GCA in patients with and without somatic mutations across the spectrum of CH to HM, we performed targeted sequencing of blood samples and electronic health record review on 114 patients with GCA seen at our institution. We then examined associations between specific clonal mutations and GCA disease manifestations. Results: UKB participants with CH had a 1.48-fold increased risk of incident GCA compared to UKB participants without CH. GCA risk was highest among individuals with cytopenia (hazard ratio [HR] 2.98, P = 0.00178) and with TET2 mutation (HR 2.02, P = 0.00116). Mutations were detected in 27.2% of our institutional GCA cohort, three of whom had HM at GCA diagnosis. TET2 mutations were associated with vision loss in patients with GCA (odds ratio 4.33, P = 0.047). Conclusions: CH increases risk for development of GCA in a genotype-specific manner, with the greatest risk being conferred by the presence of mutations in TET2. Somatic TET2 mutations likewise increase the risk of GCA-associated vision loss. Integration of somatic genetic testing in GCA diagnostics may be warranted in the future.
MeSH term(s)	Humans ; Giant Cell Arteritis/complications ; Mutation ; DNA-Binding Proteins/genetics ; Dioxygenases
Chemical Substances	TET2 protein, human (EC 1.13.11.-) ; DNA-Binding Proteins ; Dioxygenases (EC 1.13.11.-)
Language	English
Publishing date	2024-02-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2756371-6
ISSN	2326-5205 ; 2326-5191
ISSN (online)	2326-5205
ISSN	2326-5191
DOI	10.1002/art.42738
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Article ; Online: Molecular mechanism of phosphopeptide neoantigen immunogenicity.

Nature communications

2023 Volume 14, Issue 1, Page(s) 3763

Abstract: Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid ... ...

Abstract	Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid leukemia phosphoneoantigen, pMLL
MeSH term(s)	Humans ; Phosphopeptides/metabolism ; Receptors, Antigen, T-Cell ; Protein Binding
Chemical Substances	Phosphopeptides ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-06-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-39425-1
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Article ; Online: Molecular mechanism of phosphopeptide neoantigen immunogenicity

Yury Patskovsky / Aswin Natarajan / Larysa Patskovska / Samantha Nyovanie / Bishnu Joshi / Benjamin Morin / Christine Brittsan / Olivia Huber / Samuel Gordon / Xavier Michelet / Florian Schmitzberger / Robert B. Stein / Mark A. Findeis / Andy Hurwitz / Marc Van Dijk / Jennifer S. Buell / Dennis Underwood / Michelle Krogsgaard

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 18

Abstract: Abstract Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute ... ...

Abstract	Abstract Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid leukemia phosphoneoantigen, pMLL747–755 (EPR(pS)PSHSM), is recognized by a cognate T cell receptor named TCR27, a candidate for cancer immunotherapy. We show that the replacement of phosphoserine P4 with serine or phosphomimetics does not affect pMHC conformation or peptide-MHC affinity but abrogates TCR27-dependent T cell activation and weakens binding between TCR27 and pMHC. Here we describe the crystal structures for TCR27 and cognate pMHC, map of the interface produced by nuclear magnetic resonance, and a ternary complex generated using information-driven protein docking. Our data show that non-covalent interactions between the epitope phosphate group and TCR27 are crucial for TCR specificity. This study supports development of new treatment options for cancer patients through target expansion and TCR optimization.
Keywords	Science ; Q
Subject code	570
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Distinction of lymphoid and myeloid clonal hematopoiesis.

Niroula, Abhishek / Sekar, Aswin / Murakami, Mark A / Trinder, Mark / Agrawal, Mridul / Wong, Waihay J / Bick, Alexander G / Uddin, Md Mesbah / Gibson, Christopher J / Griffin, Gabriel K / Honigberg, Michael C / Zekavat, Seyedeh M / Paruchuri, Kaavya / Natarajan, Pradeep / Ebert, Benjamin L

Nature medicine

2021 Volume 27, Issue 11, Page(s) 1921–1927

Abstract: Clonal hematopoiesis (CH) results from somatic genomic alterations that drive clonal expansion of blood cells. Somatic gene mutations associated with hematologic malignancies detected in hematopoietic cells of healthy individuals, referred to as CH of ... ...

Abstract	Clonal hematopoiesis (CH) results from somatic genomic alterations that drive clonal expansion of blood cells. Somatic gene mutations associated with hematologic malignancies detected in hematopoietic cells of healthy individuals, referred to as CH of indeterminate potential (CHIP), have been associated with myeloid malignancies, while mosaic chromosomal alterations (mCAs) have been associated with lymphoid malignancies. Here, we analyzed CHIP in 55,383 individuals and autosomal mCAs in 420,969 individuals with no history of hematologic malignancies in the UK Biobank and Mass General Brigham Biobank. We distinguished myeloid and lymphoid somatic gene mutations, as well as myeloid and lymphoid mCAs, and found both to be associated with risk of lineage-specific hematologic malignancies. Further, we performed an integrated analysis of somatic alterations with peripheral blood count parameters to stratify the risk of incident myeloid and lymphoid malignancies. These genetic alterations can be readily detected in clinical sequencing panels and used with blood count parameters to identify individuals at high risk of developing hematologic malignancies.
MeSH term(s)	Blood Cell Count ; Chromosome Aberrations ; Clonal Hematopoiesis/genetics ; Clonal Hematopoiesis/physiology ; Hematologic Neoplasms/genetics ; Hematologic Neoplasms/pathology ; Hematopoietic Stem Cells/cytology ; Humans
Language	English
Publishing date	2021-10-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-021-01521-4
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Zs.A 4212: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 39: Show issues

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Article ; Online: TET2-mutant clonal hematopoiesis and risk of gout.

Blood

2022 Volume 140, Issue 10, Page(s) 1094–1103

Abstract: Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1β (IL-1β). Clonal ... ...

Abstract	Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1β (IL-1β). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1β, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177 824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: odds ratio [OR], 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: hazard ratio [HR], 1.28; 95% CI, 1.06-1.55; P = .0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1β secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1β in response to MSU crystals in vitro, which was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1β levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout.
MeSH term(s)	Animals ; Clonal Hematopoiesis ; DNA-Binding Proteins/genetics ; Dioxygenases/genetics ; Gout/genetics ; Humans ; Inflammasomes/genetics ; Interleukin-1beta/genetics ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; Uric Acid/chemistry ; Uric Acid/pharmacology
Chemical Substances	DNA-Binding Proteins ; Inflammasomes ; Interleukin-1beta ; NLR Family, Pyrin Domain-Containing 3 Protein ; Uric Acid (268B43MJ25) ; Dioxygenases (EC 1.13.11.-) ; TET2 protein, human (EC 1.13.11.-) ; Tet2 protein, mouse (EC 1.13.11.-)
Language	English
Publishing date	2022-06-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2022015384
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Zs.MO 364: Show issues

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Article ; Online: Structural Model of the Extracellular Assembly of the TCR-CD3 Complex

Aswin Natarajan / Vidushan Nadarajah / Klara Felsovalyi / Wenjuan Wang / Vivian R. Jeyachandran / Riley A. Wasson / Timothy Cardozo / Clay Bracken / Michelle Krogsgaard

Cell Reports, Vol 14, Iss 12, Pp 2833-

2016 Volume 2845

Abstract: Antigen recognition of peptide-major histocompatibility complexes (pMHCs) by T cells, a key step in initiating adaptive immune responses, is performed by the T cell receptor (TCR) bound to CD3 heterodimers. However, the biophysical basis of the ... ...

Abstract	Antigen recognition of peptide-major histocompatibility complexes (pMHCs) by T cells, a key step in initiating adaptive immune responses, is performed by the T cell receptor (TCR) bound to CD3 heterodimers. However, the biophysical basis of the transmission of TCR-CD3 extracellular interaction into a productive intracellular signaling sequence remains incomplete. Here we used nuclear magnetic resonance (NMR) spectroscopy combined with mutational analysis and computational docking to derive a structural model of the extracellular TCR-CD3 assembly. In the inactivated state, CD3γε interacts with the helix 3 and helix 4-F strand regions of the TCR Cβ subunit, whereas CD3δε interacts with the F and C strand regions of the TCR Cα subunit in this model, placing the CD3 subunits on opposing sides of the TCR. This work identifies the molecular contacts between the TCR and CD3 subunits, identifying a physical basis for transmitting an activating signal through the complex.
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2016-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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