Calsequestrin: a well-known but curious protein in skeletal muscle

Abstract

Calsequestrin (CASQ) was discovered in rabbit skeletal muscle tissues in 1971 and has been considered simply a passive Ca2+-buffering protein in the sarcoplasmic reticulum (SR) that provides Ca2+ ions for various Ca2+ signals. For the past three decades, physiologists, biochemists, and structural biologists have examined the roles of the skeletal muscle type of CASQ (CASQ1) in skeletal muscle and revealed that CASQ1 has various important functions as (1) a major Ca2+-buffering protein to maintain the SR with a suitable amount of Ca2+ at each moment, (2) a dynamic Ca2+ sensor in the SR that regulates Ca2+ release from the SR to the cytosol, (3) a structural regulator for the proper formation of terminal cisternae, (4) a reverse-directional regulator of extracellular Ca2+ entries, and (5) a cause of human skeletal muscle diseases. This review is focused on understanding these functions of CASQ1 in the physiological or pathophysiological status of skeletal muscle.

Prognostic factors of restrictive myopathy in thyroid eye disease

“…The expression of CASQ1 in the extraocular muscles is 4.8 times higher than that in other skeletal muscles, and anti-CASQ1 Ab is detected in 92% of TED patients showed extraocular muscle involvement 17 , 18 , 44 . Since CASQ1 is related to regulation of cytoplasmic calcium ion level in skeletal muscles, anti-CASQ1 Ab may disrupt normal skeletal muscle function by disturbing calcium ion regulation of skeletal muscles 19 . In these reasons anti-COLXIII Ab and anti-CASQ1 Ab are plausible candidates for prognostic factors of restrictive myopathy of TED.…”

“…As thyroid autoantibodies are known to play a role in pathogenesis and severity of TED 14 – 16 , other autoantibodies such as anti-calsequestrin 1 antibody (Anti-CASQ1 Ab) and anti-collagen XIII antibody (anti-COLXIII Ab) are also reported to be associated with the pathogenesis of TED 17 , 18 . Although the exact roles of these autoantibodies are still under investigation, calsequestrin 1 is found in extraocular muscle fibers and collagen XIII is in orbital fibroblasts 19 , 20 . Therefore, these antibodies might be related with the prognosis of restrictive myopathy.…”

Ca2+-dependent liquid-liquid phase separation underlies intracellular Ca2+ stores

“…CASQ1 is the most abundant Ca 2+ binding protein of the SR of skeletal muscle where it binds the majority of lumenal Ca 2+ . CASQ1 is observed in the ER of other tissues including cerebellar Purkinje neurons (2013; Woo et al, 2020). CASQ1 is highly conserved amongst vertebrates, binds calcium with high capacity (50-80 Ca 2+ /molecule) and low affinity ( K d ~ 10 3 M -1 ), and is characterized by low iso-electric point and an abundance of acidic residues (Sanchez et al, 2012; Woo et al, 2020).…”

“…CASQ1 is observed in the ER of other tissues including cerebellar Purkinje neurons (2013; Woo et al, 2020). CASQ1 is highly conserved amongst vertebrates, binds calcium with high capacity (50-80 Ca 2+ /molecule) and low affinity ( K d ~ 10 3 M -1 ), and is characterized by low iso-electric point and an abundance of acidic residues (Sanchez et al, 2012; Woo et al, 2020). Multivalent Ca 2+ binding induces reversible oligomerization to drive total ER/SR Ca 2+ stores well into the millimolar range, while buffering free lumenal Ca 2+ concentrations to consistent low millimolar levels (Woo et al, 2020).…”

“…CASQ1 is highly conserved amongst vertebrates, binds calcium with high capacity (50-80 Ca 2+ /molecule) and low affinity ( K d ~ 10 3 M -1 ), and is characterized by low iso-electric point and an abundance of acidic residues (Sanchez et al, 2012; Woo et al, 2020). Multivalent Ca 2+ binding induces reversible oligomerization to drive total ER/SR Ca 2+ stores well into the millimolar range, while buffering free lumenal Ca 2+ concentrations to consistent low millimolar levels (Woo et al, 2020). Mutation of CASQ1 results in human myopathies and deletion in animal models results in defects in skeletal muscle function and Ca 2+ handling (Barone et al, 2017; Lewis et al, 2015; Olojo et al, 2011; Paolini et al, 2007; Woo et al, 2020).…”