S100 calcium-binding protein A1

S100 calcium-binding protein A1 (S100A1) is a is_associated_with::protein which in humans is encoded by the S100A1 is_associated_with::gene.

Function
The protein encoded by this gene is a member of the S100 family of proteins containing 4 is_associated_with::EF-hand is_associated_with::calcium-binding motifs in its dimerized form. 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. 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 is_associated_with::microtubule assembly, and inhibition of is_associated_with::protein kinase C-mediated is_associated_with::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 is_associated_with::sarcoplasmic reticulum and the responsiveness of is_associated_with::myofibrils to calcium ion.

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

S100A1 structure
Like many other S100 proteins, S100A1 can exist as either a hetero or homodimer. is_associated_with::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 is_associated_with::N-terminus and a canonical EF-hand in the is_associated_with::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 is_associated_with::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 is_associated_with::beta sheet region (residues 27–29 and 68–70).

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'.

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.

Conformational change
Upon binding calcium, helix 3 of S100A1 (and most other S100 proteins as well) re-orients from being relatively antiparallel to helix 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 interact with is_associated_with::PGM1, is_associated_with::S100B,  is_associated_with::S100A4 and is_associated_with::TRPM3.