S100A1

S100A1, also known as S100 calcium-binding protein A1 is a is_associated_with::protein which in humans is encoded by the S100A1 is_associated_with::gene. S100A1 is highly expressed in cardiac and is_associated_with::skeletal muscle, and localizes to Z-discs and is_associated_with::sarcoplasmic reticulum. S100A1 has shown great promise as an effective candidate for is_associated_with::gene therapy to treat post-myocardially infarcted cardiac tissue.

Structure
S100A1 is a member of the S100 family of proteins expressed in is_associated_with::cardiac muscle, is_associated_with::skeletal muscle and brain, with highest density at Z-lines and is_associated_with::sarcoplasmic reticulum. S100A1 contains 4 is_associated_with::EF-hand is_associated_with::calcium-binding motifs in its dimerized form, and can exist as either a hetero or homodimer. The S100A1 homodimer is high affinity (nanomolar range or tighter), and is formed through is_associated_with::hydrophobic packing of an X-type 4-helix bundle created between helices 1, 1', 4, and 4'. is_associated_with::Protein nuclear magnetic resonance spectroscopy structural information on the homodimeric form of this protein shows that each monomer is helical and contains two EF-hand calcium-binding loops; one in the is_associated_with::N-terminus and a canonical is_associated_with::EF hand in the is_associated_with::C-terminus having higher is_associated_with::calcium affinity (is_associated_with::dissociation constant of roughly 20 micromolar). The two is_associated_with::EF hand domains neighbor each other in three dimensional space, and are connected to each other through a short is_associated_with::beta sheet region (residues 27–29 and 68–70).

Upon binding calcium, helix 3 of S100A1 re-orients from being relatively antiparallel to helix 4 to being roughly perpendicular. This conformational change is different from most is_associated_with::EF hands, in that the entering helix, and not the exiting helix, moves. This conformational change exposes a large hydrophobic pocket between helix 3, 4, and the hinge region of S100A1 that is involved in virtually all is_associated_with::calcium-dependent target protein interactions. These biophysical properties seem to be well conserved across the S100 family of proteins. Helix 3, 4, and the hinge region are the most divergent areas between individual S100 proteins, and so it is likely that the sequence of these regions is pivotal in fine-tuning calcium-dependent target binding by S100 proteins. Interestingly, is_associated_with::S-Nitrosylation of S100A1 at Cys85 reorganizes the conformation of S100A1 at the C-terminal helix and the linker connecting the two is_associated_with::EF hand domains.

The most accurate high-resolution solution structure of human apo-S100A1 protein (PDB accession code: 2L0P) has been determined by means of NMR spectroscopy in 2011.

S100 genes include at least 19 members which are located as a cluster on chromosome 1q21.

Function
S100 proteins are localized in the is_associated_with::cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as is_associated_with::cell cycle progression and differentiation. This protein may function in stimulation of Ca2+-induced Ca2+ release, inhibition of is_associated_with::microtubule assembly, and inhibition of is_associated_with::protein kinase C-mediated is_associated_with::phosphorylation.

S100A1 is expressed during development in the primitive heart at embryonic day 8 in levels that are similar between atria and ventricles. As development progresses up to embryonic day 17.5, S100A1 expression shifts to a lower levels in atria and higher levels in ventricular is_associated_with::myocardium.

S100A1 has shown to be a regulator of myocardial contractility. S100A1 overexpression via adenoviral gene transfer in adult rabbit is_associated_with::cardiomyocytes or a cardiac-restricted S100A1 murine transgenic enhanced cardiac contractile performance by increasing sarcoplasmic reticular is_associated_with::calcium transients and uptake, altering the is_associated_with::calcium sensitivity and cooperativity of is_associated_with::myofibrils, enhancing SERCA2A activity and enhancing is_associated_with::calcium-induced calcium release. Specifically, S100A1 increases the gain of is_associated_with::excitation-contraction coupling and decreases calcium spark frequency in is_associated_with::cardiomyocytes. Enhancement of is_associated_with::L-type calcium channel transis_associated_with::sarcolemmal is_associated_with::calcium influx by S100A has been shown to be dependent on is_associated_with::protein kinase A. Effects of S100A1 on myofilament proteins may be via is_associated_with::Titin; S100A1 has been shown to interact with the PEVK region of is_associated_with::Titin in a is_associated_with::calcium-dependent manner, and it's binding reduces the force in an in vitro motility assay, suggesting that S100A may modulate is_associated_with::Titin-based passive tension prior to is_associated_with::systole. In mice with ablation of the S100A1 gene (S100A1-/-), cardiac reserve upon beta adrenergic stimulation was impaired, showing reduced contraction rate and relaxation rate, as well as reduced is_associated_with::calcium sensitivity. However, S100A1-/- did not show the eventual is_associated_with::cardiac hypertrophy or chamber dilation in aged mice.

In animal models of disease, S100A1 is_associated_with::protein levels has been shown to be altered in right ventricular hypertrophied tissue in a model of is_associated_with::pulmonary hypertension; several tissue types (is_associated_with::brain, is_associated_with::skeletal muscle and is_associated_with::cardiac muscle) in a model of is_associated_with::type I diabetes mellitus; S100A1 has been demonstrated as a regulator of the genetic program underlying is_associated_with::cardiac hypertrophy, in that S100A1 inhibits alpha1 adrenergic stimulation of hypertrophic genes, including is_associated_with::MYH7, is_associated_with::ACTA1 and is_associated_with::S100B. In a rat model of is_associated_with::myocardial infarction, intracoronary S100A1 adenoviral gene transfer restored sarcoplasmic reticular is_associated_with::calcium transients and load, normalized intracellular is_associated_with::sodium concentrations, reversed the pathologic expression of the fetal gene program, restored energy supply, normalized contractile function, preserved inotropic reserve, and reduced is_associated_with::cardiac hypertrophy 1 week post-is_associated_with::myocardial infarction. In support of the adenoviral experiments, S100A1 transgenic overexpressing mice subjected to is_associated_with::myocardial infarction showed preserved contractile function, abrogated is_associated_with::apoptosis, preserved is_associated_with::sarcoplasmic reticulum is_associated_with::calcium cycling and beta adrenergic signaling, prevention from is_associated_with::cardiac hypertrophy and is_associated_with::heart failure, as well as prolonged survival relative to non-transgenic controls.

S100A1 has also been identified as a novel regulator of is_associated_with::endothelial cell post-ischemic is_associated_with::angiogenesis, as patients with limb ischemia exhibited downregulation of S100A1 expression in hypoxic tissue.

In melanocytic cells, S100A1 gene expression may be regulated by MITF.

Clinical Significance
S100A1 has shown efficacy in feasibility in treating is_associated_with::heart failure symptoms in large, preclinical models and human cardiomyocytes, and thus shows great promise for clinical trials.

Reduced expression of this protein has been implicated in cardiomyopathies, and is_associated_with::left ventricular assist device-based therapy does not restore S100A1 levels in patients. S100A1 has shown promise as an early diagnostic biomarker for acute is_associated_with::myocardial ischemia, presenting with a distinct timecourse in human plasma following an ischemic event relative to traditional markers is_associated_with::creatine kinase, is_associated_with::CKMB and troponin I. This injury-released, extracellular pool of S100A1 was investigated in neonatal murine is_associated_with::cardiomyocytes and was shown to prevent apoptosis via an ERK1/2-dependent pathway, suggesting that the release of S100A1 from injured cells is an intrinsic survival mechanism for viable myocardium. S100 has also shown promise as a biomarker for uncontrolled hyperoxic reoxygenation during is_associated_with::cardiopulmonary bypass in infants with is_associated_with::cyanotic heart disease and in adults. S100A1 gene transfer to engineered heart tissue was shown to augment contractile performance of the tissue implants, suggesting that S100A1 may be effective in facilitating cardiac tissue replacement therapy in is_associated_with::heart failure patients. However, the clinical efficacy of this strategy remains to be determined. In addition, multiple drugs, including is_associated_with::Pentamidine, is_associated_with::Amlexanox, is_associated_with::Olopatadine, is_associated_with::Cromolyn, and is_associated_with::Propanolol, are known to bind to S100A1, although their affinities are often in the mid-micromolar range.

Interactions
S100 interacts with
 * is_associated_with::PGM1
 * is_associated_with::S100B
 * is_associated_with::S100A4
 * is_associated_with::TRPM3
 * is_associated_with::Titin
 * is_associated_with::RYR2
 * SERCA2A
 * is_associated_with::PLB
 * is_associated_with::RYR1