Last update 19 Sep 2024

CASQ2

Last update 19 Sep 2024

Basic Info

Synonyms

calsequestrin 2, Calsequestrin-2, Calsequestrin, cardiac muscle isoform

+ [2]

Introduction

Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle. Calcium ions are bound by clusters of acidic residues at the protein surface, especially at the interface between subunits. Can bind around 60 Ca(2+) ions. Regulates the release of lumenal Ca(2+) via the calcium release channel RYR2; this plays an important role in triggering muscle contraction. Plays a role in excitation-contraction coupling in the heart and in regulating the rate of heart beats.

Drugs associated with CASQ2

AT-307

Target

CASQ2

Mechanism

CASQ2 modulators

Active Org.-

Originator Org.

Fondazione Salvatore Maugeri Clinica del Lavoro e della Riabil

Active Indication-

Inactive Indication

Tachycardia, Ventricular

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with CASQ2

100 Translational Medicine associated with CASQ2

0 Patents (Medical) associated with CASQ2

324

Literatures (Medical) associated with CASQ2

01 Sep 2024·Journal of Human Genetics

Whole genome sequencing of families diagnosed with cardiac channelopathies reveals structural variants missed by whole exome sequencing

Article

Author: Vr, Arvinden ; Shenthar, Jeyaprakash ; Sharma, Gautam ; Sivasubbu, Sridhar ; Jolly, Bani ; Bajaj, Anjali ; Mp, Jayakrishnan ; Kumar, Kapil ; Naik, Nitish ; Rai, Nitin ; Abqari, Shaad ; Imran, Mohamed ; Krishna, Maniram ; Ali, Muzaffar ; Divakar, Mohit Kumar ; Bhoyar, Rahul ; Vignesh, Harie ; Scaria, Vinod ; Senthivel, Vigneshwar ; Nadri, Gulnaz

Cardiac channelopathies are a group of heritable disorders that affect the heart's electrical activity due to genetic variations present in genes coding for ion channels. With the advent of new sequencing technologies, molecular diagnosis of these disorders in patients has paved the way for early identification, therapeutic management and family screening. The objective of this retrospective study was to understand the efficacy of whole-genome sequencing in diagnosing patients with suspected cardiac channelopathies who were reported negative after whole exome sequencing and analysis. We employed a 3-tier analysis approach to identify nonsynonymous variations and loss-of-function variations missed by exome sequencing, and structural variations that are better resolved only by sequencing whole genomes. By performing whole genome sequencing and analyzing 25 exome-negative cardiac channelopathy patients, we identified 3 pathogenic variations. These include a heterozygous likely pathogenic nonsynonymous variation, CACNA1C:NM_000719:exon19:c.C2570G:p. P857R, which causes autosomal dominant long QT syndrome in the absence of Timothy syndrome, a heterozygous loss-of-function variation CASQ2:NM_001232.4:c.420+2T>C classified as pathogenic, and a 9.2 kb structural variation that spans exon 2 of the KCNQ1 gene, which is likely to cause Jervell-Lange-Nielssen syndrome. In addition, we also identified a loss-of-function variation and 16 structural variations of unknown significance (VUS). Further studies are required to elucidate the role of these identified VUS in gene regulation and decipher the underlying genetic and molecular mechanisms of these disorders. Our present study serves as a pilot for understanding the utility of WGS over clinical exomes in diagnosing cardiac channelopathy disorders.

01 Aug 2024·Protein Science

Stable and reusable calcium‐responsive biopolymer for affinity precipitation of therapeutic antibodies

Article

Author: Lee, Jonghwan ; Oh, Jeong-Seok ; Park, Seho ; Park, Keunwan ; Bang, Jinho ; Park, Heesun ; Woo, Jae-Sung ; Jeong, Suhyeon ; Kim, Sunghyun

AbstractAffinity precipitation is an attractive method for protein purification due to its many advantages, including the rapid capture of target proteins, simple processing, high specificity, and ease of scale‐up. We previously reported a robust antibody purification method using Ca2+‐dependent precipitation of ZZ‐hCSQ2, a fusion protein of human calsequestrin 2, and the antibody‐binding protein ZZ. However, the stability of this fusion protein was not sufficiently high for industrial use because the antibody recovery yield decreased to 60% after being reused 10 times. To identify a more stable calsequestrin (CSQ), we calculated Rosetta energy values for the folding stabilities of various CSQ homologs and selected human CSQ1 (hCSQ1) with lowest energy value (−992.6) as the new CSQ platform. We also identified that the linker sequence between ZZ and CSQ was vulnerable to proteases and alkaline pH by N‐terminal protein sequencing. Therefore, we changed the linker to four asparagine (4N) sequences, which were shorter and less flexible than the previous glycine‐rich linker. The new version of ZZ‐CSQ, ZZ‐4N‐hCSQ1, was stable in a protease‐containing conditioned medium obtained from the cultured Chinese hamster ovary cell or high pH condition (0.1M sodium hydroxide) for more than 5 days and could be reused at least 25 times for antibody purification without loss of recovery yield. The antibodies purified by ZZ‐4N‐hCSQ1 precipitation also showed greater purity (~33.6‐fold lower host cell DNA and ~6.4‐fold lower host cell protein) than those purified by protein A chromatography. These data suggest that ZZ‐4N‐hCSQ1 precipitation is more efficient and can achieve cost‐effectiveness of up to 12.5‐fold cheaper than previous antibody purification methods and can lower the production costs of therapeutic antibodies.

01 Aug 2024·Journal of Biochemical and Molecular Toxicology

CASQ2 alleviates lung cancer by inhibiting M2 tumor‐associated macrophage polarization and JAK/STAT pathway

Article

Author: Yan, Jun ; Ding, Yan ; Yuan, Xiaoliang ; Wang, Ying

AbstractLung cancer (LC) is a major inducer of cancer‐related death. We aim to reveal the effect of Calsequestrin2 (CASQ2) on macrophage polarization and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in LC. Hub genes were determined from protein–protein interaction networks based on GSE21933 and GSE1987 data sets using bioinformatic analysis. Expression of hub genes was verified by real‐time quantitative polymerase chain reaction (RT‐qPCR). Cell Counting Kit‐8, 5‐ethynyl‐2'‐deoxyuridine, wound‐healing, colony formation, and transwell assays were performed to assess the impact of CASQ2 on LC cells. A xenograft mouse model was evaluated using hematoxylin–eosin, immunohistochemistry, and terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling staining to investigate the effect of CASQ2 on LC. The role of CASQ2 in regulating macrophage polarization and JAK/STAT pathway was evaluated by western blot andRT‐qPCR. We screened out 155 common differentially expressed genes in GSE21933 and GSE1987 data sets. Myomesin‐2, tyrosine kinase, sex determining region Y‐box 2, platelet and endothelial cell adhesion molecule 1, matrix metallopeptidase 9, claudin‐5, caveolin‐1, CASQ2, recombinant ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 (ATP2A2), and ankyrin repeat domain 1 were identified as the hub genes with high prediction value. CASQ2 was selected as a pivotal regulator of LC. In vitro experiments and xenograft models revealed that CASQ2 overexpression suppressed proliferation, colony formation, migration, invasion of LC cells, and tumor growth in vivo. Additionally, overexpression of CASQ2 promoted the expression of M1 macrophage markers (cluster of differentiation 80 [CD80], interleukin [IL]‐12, inducible nitric oxide synthase [iNOS]), while decreasing the expression of M2 macrophage markers (CD163, IL‐10, Arg1) in tumor‐associated macrophages and xenograft tissues. Finally, we found that overexpression of CASQ2 inhibited JAK/STAT pathway. CASQ2 is a novel biomarker, which can alleviate LC via inhibiting M2 tumor‐associated macrophage polarization and JAK/STAT pathway.

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CASQ2

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