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8.A.88.1.5
Calsequestrin 2, CSR2, CASQ2 of 399 aas and possibly one N-terminal TMS. While CSR1 (TC# 8.A.88.1.1) is found in the sarcoplasmic reticulum (SR) lumen of skeletal muscle, and possibly in the SR lumen of cardiac muscle (Chen and Kudryashev 2020). CSQ2) is a Ca2+-binding protein suppling Ca2+ for ryanodine receptor Ca2+ release during the excitation-contraction coupling in cardiomyocytes. CSQ2 mutations causes catecholaminergic polymorphic ventricular tachycardia (CPVT2), suggesting that it may function beyond that of a Ca2+ buffer. Fan et al. 2022 identified a non-transmembrane channel in Ca2+-enriched CSQ2 dimers, which facilitates fast Ca2+ mobilization. Using crystallography, they solved the high-resolution structure of Ca2+-bound CSQ2 and discovered that the negatively charged residues at the dimer interface encompassed a tubular channel-like structure, dubbed "tunnel," in which approximately 15 Ca2+ ions aligned across the approximately 5 nm tunnel path. To determine the potential tunnel conductance, the authors developed a graphene-based nanoelectronic technology to connect a CSQ2 dimer into a nanocircuit. In the Tyrode solution containing 1 mM Ca2+, a CSQ2 dimer exhibited a conductance one order of magnitude higher than the background level. This conductance was Ca2+ dependent, and was largely suppressed by the single-residue mutation D309N at the bottleneck region of the tunnel path, indicating that the tunnel conducted Ca2+ fluxes. When the D309N mutant CSQ2 was expressed in wild-type rat cardiomyocytes, isoproterenol treatment induced chaotic Ca2+ waves, delayed after-depolarizations and trigged activities resembling those occurring in CPVT2 models. This dominant negative effect of the CSQ2 mutation agreed well with the structural observation that CSQ2 tunnels were interconnected to form a tunnel network. Thus, CSQ2 builds a nano-highway network for energy-efficient Ca2+ mobilization in the SR. Factors that block the Ca2+ highway may lead to arrhythmogenesis (Fan et al. 2022).

Accession Number:O14958
Protein Name:Calsequestrin-2
Length:399
Molecular Weight:46436.00
Species:Homo sapiens (Human) [9606]
Location1 / Topology2 / Orientation3: Sarcoplasmic reticulum lumen1
Substrate

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FASTA formatted sequence
1:	MKRTHLFIVG IYFLSSCRAE EGLNFPTYDG KDRVVSLSEK NFKQVLKKYD LLCLYYHEPV 
61:	SSDKVTQKQF QLKEIVLELV AQVLEHKAIG FVMVDAKKEA KLAKKLGFDE EGSLYILKGD 
121:	RTIEFDGEFA ADVLVEFLLD LIEDPVEIIS SKLEVQAFER IEDYIKLIGF FKSEDSEYYK 
181:	AFEEAAEHFQ PYIKFFATFD KGVAKKLSLK MNEVDFYEPF MDEPIAIPNK PYTEEELVEF 
241:	VKEHQRPTLR RLRPEEMFET WEDDLNGIHI VAFAEKSDPD GYEFLEILKQ VARDNTDNPD 
301:	LSILWIDPDD FPLLVAYWEK TFKIDLFRPQ IGVVNVTDAD SVWMEIPDDD DLPTAEELED 
361:	WIEDVLSGKI NTEDDDEDDD DDDNSDEEDN DDSDDDDDE