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Research Themes Protein design

Secretagogin

PSI-SGKB [doi:10.3942/psi_sgkb/fm_2009_12]
Featured System - December 2009
Short description: Cells typically deplete themselves of calcium, expending considerable energy to pump calcium ions out of the cell or into special compartments inside the cell.

Cells typically deplete themselves of calcium, expending considerable energy to pump calcium ions out of the cell or into special compartments inside the cell. This provides a powerful method to propagate signals throughout the cell: when the cell lets calcium back in, the fast-moving calcium ions spread quickly to all corners. For instance, you experience the speed and efficiency of calcium signaling with every beat of your heart. A wave of calcium ions flows through the muscle cells, causing them to contract. Calcium ions are also used for many other signaling tasks at all stages of our life, from the fertilization of eggs to our last thoughts.

Sensing Calcium

Of course, calcium ions alone are not enough. These waves of calcium ions need to be sensed and used to perform a useful task. The protein secretagogin is one of many sensors that monitor the level of calcium ions inside cells. It is thought to regulate the release of vesicles, such as insulin secretory vesicles or neurotransmitter vesicles. When it binds to calcium, it changes into an active shape that binds about ten times more tightly to SNAP-25, a protein that mediates fusion of vesicles to the cell surface.

Giving the Cell a Hand

Researchers at the CESG have solved the structure of zebrafish secretagogin (PDB entry 2be4), giving an atomic-level look at its multiple calcium binding sites. Secretagogin is composed of six calcium-binding motifs (each a different color in the images here) strung together by short protein linkers. Each of these motifs, often referred to as an "EF-hand", is composed of two short alpha helices connected by a characteristic loop. The loop contains five conserved residues that coordinate with calcium, typically acidic amino acids or amino acids with oxygen atoms in their sidechains (as shown in the Jmol image below). In the secretegogin structure, no calcium is bound and these residues are randomly arrayed around this loop. But when calcium binds, these amino acids will be brought together in a tight octahedral arrangement around the ion, shifting the protein into its active form.

Better in Pairs

Looking at the many examples of calcium-binding proteins that are available in the PDB, we find that EF-hands nearly always come in pairs. In these paired arrangements, the two calcium bindings motifs stabilize each other through a series of hydrogen bonds and hydrophobic interactions. Secretagogin has six EF-hands, paired to form three tight domains. Based on a comparison of this structure with calbindin D28K, another protein with six EF-hands, signaling by secretagogin may involve a large motion of the first domain (EF1 and EF2) when the protein binds to calcium.

The JSmol tab below displays an interactive JSmol.

Alg12 and MurG (PDB entries 2jzc and 1nlm)

Alg13 (turquoise) is overlapped with the C-terminal domain of the bacterial enzyme MurG (red). The MurG structure includes a sugar-nucleotide donor bound in the active site, shown here in green. Use the buttons below to flip between different representations of the structures, and to highlight the two beta sheets in Alg13 that are different than the typical glycosylase fold.

References

  1. Bitto, E., Bingman, C. A., Bittova, L., Frederick, R. O., Fox, B. G., Phillips, G. N. (2009) X-ray structure of Danio rerio secretagogin: A hexa-EF-had calcium sensor. Proteins 76, 477-483.

  2. Gifford, J. L., Walsh, M. P., Vogel, H. J. (2007) Structures and metal-ion-binding properties of the Ca2+-binding helix-loop-helix EF-hand motifs. Biochem. J. 405, 199-221.

  3. Berridge, M. J., Lipp, P., Bootman, M. D. (2000) The versatility and universality of calcium signalling. Nat. Rev. Mol. Cell Biol. 1, 11-21.

  4. Charette, M. and Gray, M. W. (2000) Pseudouridine in RNA: what, where, how, and why. IUBMB Life 49, 341-351.

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