Calcium protein motifs 356

One of these motifs, called the helix-turn-helix motif, is specific for DNA binding and is described in detail in Chapters 8 and 9. The second motif is specific for calcium binding and is present in parvalbumin, calmodulin, tro-ponin-C, and other proteins that bind calcium and thereby regulate cellular activities. This calcium-binding motif was first found in 1973 by Robert Kretsinger, University of Virginia, when he determined the structure of parvalbumin to 1.8 A resolution. 

Figure 2.12 Two a helices that are connected by a short loop region in a specific geometric arrangement constitute a helix-turn-helix motif. Two such motifs are shown the DNA-binding motif (a), which is further discussed in Chapter 8, and the calcium-binding motif (b), which is present in many proteins whose function is regulated by calcium.

Nalefski, E.A., and FaUce, J.J., 1996, The C2 domain calcium-binding motif structural and functional diversity. Protein Sci. 5 2375-2390. 

FIGURE 17.20. An EF hand, a calcium-binding motif in proteins, (a) Ligands binding to each coordination position around Ca +, and (b) the sequence numbering (starting at 6 and proceeding to - -5) of the protein as it binds to Ca +... 

Proteins are constructed of modular systems or domains. These are portions of the polypeptide chain that can fold independendy into a stable structure. A protein may be just one domain, or may be comprised of many domains. A typical domain may be roughly 25 A in diameter and consist of 100-150 amino acid residues. For example, two a helices, joined by a loop (the helix-loop-helix motif) can give a calcium-binding motif or a DNA-binding motif. The so called Greek key motif consists of four antiparallel P strands arranged in a pattern reminiscent of one found in ancient Greekffiezes (80). The PaP motif consists of two P strands that are parallel but not necessarily adjacent connected by an a helix, which shields the strands from solvent. Some examples of these types of motifs are shown in Fig. 33. 

Fig. 15.11. Ribbon diagrams [54]. Left calcium-binding motif (residues 78-108) of carp parval-bumin (4CPV) right DNA binding motif (residues 168-191) of catabolite gene activator protein (3 GAP)...

Several calcium-binding motifs have been characterized for proteins especially those with regulatory roles. The structural chemistry of EF hands and the coordination chemistry of calcium and other spherical metal ions, and related models, have been reviewed by Falke. " ... 

One calcium-binding motif found in proteins is the helixloophelix motif, also known as an EF hand [74, 75]. A comparison, diagrammed in Fig. 29, is made... 

Figure 2. Frequency distributions for ranking of motifs in order of decreasing similarity with part of a calcium>binding domain found within the muscle protein Troponin-C (called here TNC2). The distributions represent the hits that came (a) second (b) sixth (c) eleventh (d) thirty-fifth and (e) sixty-ninth. In each case, the distribution for the query motif is shown by a dashed fine and that for the database protein motif by a continuous fine.

Parvalbumin is a muscle protein with a single polypeptide chain of 109 amino acids. Its function is uncertain, but calcium binding to this protein probably plays a role in muscle relaxation. The helix-loop-helix motif appears three times in this structure, in two of the cases there is a calcium-binding site. Figure 2.13 shows this motif which is called an EF hand because the fifth and sixth helices from the amino terminus in the structure of parvalbumin, which were labeled E and F, are the parts of the structure that were originally used to illustrate calcium binding by this motif. Despite this trivial origin, the name has remained in the literature. 

Table 2.2 Amino acid sequences of calcium-binding EF motifs in three different proteins Pamalbumin VKKAFAI I DQDKSGFIEEDELKLFLQNF Calmodulin FKEAFSLFDKDGDGT I TTKELGTVMRSL Troponin-C LADCFR I FDKNADGF I D lEELGE I LRAT...

Boumann, U., et al. Three-dimensional structure of the alkaline protease of Pseudomonas aeruginosa, a two-domain protein with a calcium binding parallel beta roll motif. EMBO J. 12 3357-3364, 1993. 

Recent interest has focused on acidic phosphoproteins, such as bone sialoprotein, acting as sites of nucleation. These proteins contain motifs (eg, poly-Asp and poly-Glu stretches) that bind calcium and may provide an initial scaffold for mineralization. Some macromolecules, such as certain proteoglycans and glycoproteins, can also act as inhibitors of nucleation. 

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