S100A1
Encyclopedia
S100 calcium-binding protein A1, also known as S100A1, is a protein
which in humans is encoded by the S100A1 gene
.
of proteins containing 2 EF-hand calcium
-binding motifs
. S100 proteins are localized in the cytoplasm
and/or nucleus
of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle
progression and differentiation
. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in stimulation of Ca2+-induced Ca2+ release, inhibition of microtubule
assembly, and inhibition of protein kinase C
-mediated phosphorylation
. Reduced expression of this protein has been implicated in cardiomyopathies
.
S100A1 overexpression enhances cardiac contractile performance
which suggests that S100A1 is a regulator of myocardial contractility. S100A1 improves cardiac performance both by regulating calcium ion handling by the sarcoplasmic reticulum and the responsiveness of myofibril
s to calcium ion.
In melanocytic
cells, S100A1 gene expression may be regulated by MITF
.
. Protein nuclear magnetic resonance spectroscopy
structural information on the homodimeric form of this protein shows that each monomer is quite helical, and contains two EF-hand calcium-binding loops; an 'S100' EF hand in the N-terminus and a canonical EF-hand in the C-terminus. These domains
are linked by a 'hinge' region, which exists as a random coil. Both EF-hands bind calcium, although the real EF-hand has a significantly higher affinity (with a dissociation constant
of roughly 20 micromolar). The two calcium-binding regions neighbor each other in three dimensional space, and are connected to each other through a short beta sheet
region (residues 27–29 and 68–70).
The S100A1 homodimer is high affinity (nanomolar range or tighter), and is formed through hydrophobic packing of an X-type 4-helix bundle created between helices 1, 1', 4, and 4'.
Recently the most accurate high-resolution solution structure of human apo-S100A1 protein (PDB accesion code: 2L0P) has been determined by means of NMR spectroscopy (ref. Nowakowski, M., Jaremko, L., Jaremko, M., Zhukov, I., Belczyk, A., Bierzynski, A,. Ejchart, A. Solution NMR structure and dynamics of human apo-S100A1 protein., J. Struct. Biol. 2011, 174, 391-399, doi: 10.1016/j.jsb.2011.01.011).
4 to being roughly perpendicular. This conformational change is different from most 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 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.
with PGM1
, S100B
and S100A4
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
which in humans is encoded by the S100A1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
The protein encoded by this gene is a member of the S100 familyS-100 protein
S-100 protein is a family of low molecular weight protein found in vertebrates characterized by two calcium binding sites of the helix-loop-helix conformation. There are at least 21 different types of S100 proteins...
of proteins containing 2 EF-hand calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
-binding motifs
Structural motif
In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a supersecondary structure, which appears also in a variety of other molecules...
. S100 proteins are localized in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
and/or nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
progression and differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in stimulation of Ca2+-induced Ca2+ release, inhibition of microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
assembly, and inhibition of protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
-mediated phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
. Reduced expression of this protein has been implicated in cardiomyopathies
Cardiomyopathy
Cardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
.
S100A1 overexpression enhances cardiac contractile performance
Contractility
Myocardial contractility is the intrinsic ability of the heart to contract independent of preload and afterload. Changes in the ability to produce force during contraction result from different degrees of binding between myosin and actin filaments...
which suggests that S100A1 is a regulator of myocardial contractility. S100A1 improves cardiac performance both by regulating calcium ion handling by the sarcoplasmic reticulum and the responsiveness of myofibril
Myofibril
A myofibril is a basic unit of a muscle. Muscles are composed of tubular cells called myocytes or myofibers. Myofibers are composed of tubular myofibrils. Myofibrils are composed of long proteins such as actin, myosin, and titin, and other proteins that hold them together...
s to calcium ion.
In melanocytic
Melanocytic nevus
A melanocytic nevus is a type of lesion that contains nevus cells .Some sources equate the term mole with "melanocytic nevus". Other sources reserve the term "mole" for other purposes....
cells, S100A1 gene expression may be regulated by MITF
Microphthalmia-associated transcription factor
Microphthalmia-associated transcription factor is a basic helix-loop-helix leucine zipper transcription factor involved in melanocyte and osteoclast development.-Clinical significance:...
.
S100A1 structure
Like many other S100 proteins, S100A1 can exist as either a hetero or homodimerProtein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
. Protein nuclear magnetic resonance spectroscopy
Protein nuclear magnetic resonance spectroscopy
Nuclear magnetic resonance spectroscopy of proteins is a field of structural biology in which NMR spectroscopy is used to obtain information about the structure and dynamics of proteins. The field was pioneered by Richard R. Ernst and Kurt Wüthrich, among others...
structural information on the homodimeric form of this protein shows that each monomer is quite helical, and contains two EF-hand calcium-binding loops; an 'S100' EF hand in the N-terminus and a canonical EF-hand in the C-terminus. These domains
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
are linked by a 'hinge' region, which exists as a random coil. Both EF-hands bind calcium, although the real EF-hand has a significantly higher affinity (with a dissociation constant
Dissociation constant
In chemistry, biochemistry, and pharmacology, a dissociation constant is a specific type of equilibrium constant that measures the propensity of a larger object to separate reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into...
of roughly 20 micromolar). The two calcium-binding regions neighbor each other in three dimensional space, and are connected to each other through a short beta sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
region (residues 27–29 and 68–70).
The S100A1 homodimer is high affinity (nanomolar range or tighter), and is formed through hydrophobic packing of an X-type 4-helix bundle created between helices 1, 1', 4, and 4'.
Recently the most accurate high-resolution solution structure of human apo-S100A1 protein (PDB accesion code: 2L0P) has been determined by means of NMR spectroscopy (ref. Nowakowski, M., Jaremko, L., Jaremko, M., Zhukov, I., Belczyk, A., Bierzynski, A,. Ejchart, A. Solution NMR structure and dynamics of human apo-S100A1 protein., J. Struct. Biol. 2011, 174, 391-399, doi: 10.1016/j.jsb.2011.01.011).
Conformational change
Upon binding calcium, helix 3 of S100A1 (and most other S100 proteins as well) re-orients from being relatively antiparallel to helixAlpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
4 to being roughly perpendicular. This conformational change is different from most 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 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.
Interactions
S100 calcium-binding protein A1 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with PGM1
PGM1
Phosphoglucomutase-1 is an enzyme that in humans is encoded by the PGM1 gene.-Interactions:PGM1 has been shown to interact with S100 calcium binding protein A1 and S100B.-Further reading:...
, S100B
S100B
S100 calcium binding protein B or S100B is a protein of the S-100 protein family.S100 proteins are localized in the cytoplasm and nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation...
and S100A4
S100A4
Protein S100-A4 is a protein that in humans is encoded by the S100A4 gene.-Interactions:S100A4 has been shown to interact with S100 calcium binding protein A1.-Further reading:...
.