302 GROUP I AND II METALS IN BIOLOGICAL SYSTEMS: GROUP II
adult cardiac SR. It binds calcium with high capacity and low affi nity during
muscle relaxation. Table 6.6 of reference 1 collects some information on
calcium - binding proteins. Chapter 6 of reference 66 discusses calcium -
containing biomolecules and its Chapter 7 discusses calcium ions as secondary
messengers.
6.3.2 Calmodulin,
6.3.2.1 Introduction. Calmodulin (CaM) is a small acidic protein of 148
amino acid residues weighing approximately 17 kDa. CaM is present in all
eukaryotic cells, serves as a primary receptor for intracellular Ca 2+ , and acts
as a switch in cellular processes controlled by Ca 2+ - dependent signaling path-
ways. In the calcium - saturated state, Ca 2+ - CaM can interact with and modulate
many different proteins including adenylate cyclase, nitric oxide synthetases,
phophodiesterases, and calcium pumps (to be discussed in the Section 6.4.2),
as well as assorted kinases and phosphatases.^67 Ca 2+ - CaM activates its target
proteins by interacting with peptide sequences within the targets that have a
high degree of helicity when they are bound to calmodulin.^68 Because calmod-
ulin binds to so many different proteins, its structure must carry a great deal
of fl exibility and this factor will become evident in the discussion that follows.
The binding of calcium ions causes major changes in calmoldulin ’ s tertiary
structure, exposing hydrophobic surfaces for interaction with enzyme target
substrates. To understand CaM ’ s activity, researchers have studied binding of
drug molecules (agonists or antagonists) or small peptides to CaM. An agonist
may be defi ned as a drug that binds to a receptor of a cell and triggers a
response by the cell. An agonist often mimics the action of a naturally occur-
ring substance. An antagonist may be defi ned as a drug that binds to a cell
receptor without eliciting a biological response.
In calmodulin, four calcium ions bind to four EF - hand motifs with micro-
molar affi nity. The calcium ion binding lobes have strong resemblance to
those of troponin C (TnC). Troponin researchers note that the arrangement
of troponin ’ s TnC lobes strongly resembles those of calmodulin, especially
after rearrangement of TnC induced by TnC/TnI 1 – 47 complex formation.^69
Troponin consists of three subunits: (1) Troponin C, the Ca 2+ binding subunit
(TnC, 18.4 kDa), Troponin I, the inhibitory subunit (TnI, ∼ 20 – 25 kDa), and
Troponin T, the tropomyosin - binding subunit (TnT, ∼ 31 – 33 kDa). In muscle,
troponin and tropomyosin units bind to the actin - containing muscle thin fi la-
ment. Polymerized actin forms the backbone of this thin fi lament. Troponin
and tropomyosin units are located at points along polymerized actin at a tro-
ponin:tropomyosin:actin ratio of 1:1:7.^70 The two proteins, calmodulin and
troponin, have distinct biological functions. Calmodulin functions as an iso-
lated protein and both of its binding lobes serve signaling functions. In con-
trast, TnC is part of the larger troponin complex and only its N - terminal lobes
(sites I and II) play a regulatory role. TnC ’ s C - terminal binding sites (sites III
and IV) play a structural role and integrate TnC into the rest of the troponin
complex.