Calmodulin (also referred to as CaM) is a small, essential Ca2+ binding protein encoded by CMD1 that regulates many processes including response to various stress conditions, mating, budding, and actin-based processes (7). This wide range of roles is possible because calmodulin undergoes a conformational change upon calcium binding. The apo-calcium form has a very different structure than the calcium bound form and thus binds to a different set of protein targets (7). Although calmodulin is essential (3, 4), the essential functions mediated by calmodulin do not require calcium-binding, as cells with mutant forms of calmodulin which lack the ability to bind Ca2+ are viable and have only minor defects in growth and morphology in standard laboratory conditions (11). Some of the Ca2+-dependent targets of calmodulin only become essential in response to various stress conditions (7). Thus calmodulin has many targets, both Ca2+-dependent and Ca2+-independent.

Ca2+-independent roles of Calmodulin

Ca2+-independent targets of calmodulin, some of which are essential genes, play roles in the organization and formation of the spindle pole body (SPB), karyogamy, actin cytoskeletal organization and bud emergence, endocytosis, and microautophagy. Calmodulin localizes to the central plaque of the spindle pole body through its interaction with Spc110p (12, 13). Binding by calmodulin is required for correct localization of the essential Spc110p component to the SPB and thus the formation of the SPB (7, 14) and also for karyogamy (15). Calmodulin also interacts with Myo2p, one of two type V myosin heavy chains (16). Through its interaction with Myo2p, calmodulin is required for polarized growth of yeast cells and inheritance of the vacuole by daughter cells (7). Calmodulin may also interact with the other type V heavy chain encoded by Myo4p (7). Through interactions with both the unconventional type I myosin, encoded by MYO5, and Arc35p, a component of the Arp2/3 complex, calmodulin is also required for receptor-mediated endocytosis (17, 2, 7). Calmodulin is also involved in microautophagy, a role which may be mediated by Vtc2p and Vtc3p (18).

Ca2+-dedependent roles of Calmodulin

Calmodulin also has multiple Ca2+-dependent targets, including calcineurin and calmodulin-stimulated protein kinases. Calcineurin, or PP2B, is a Ca2+ and calmodulin dependent phosphatase that is highly conserved amongst eukaryotic organisms and regulates many different processes. Calcineurin is composed of a heterodimer of a catalytic A subunit, encoded by CMP2 and CNA1, and a regulatory B subunit, encoded by CNB1, which is an EF-hand domain protein related to calmodulin. When stimulatory levels of Ca2+ are present, calcium-bound calmodulin binds to the A subunit, displacing an autoinhibitory domain of the A subunit. In yeast, calcineurin regulates at least three different processes: a stress-activated transcriptional pathway, calcium homeostasis, and the G2 to M transition of the cell cycle. Calmodulin also regulates calcium and calmodulin dependent kinases, of which there are two in S. cerevisiae, encoded by CMK1 and CMK2. In the presense of calcium and calmodulin, they become autophosphorylated and can phosphorylate many different substrates. The calmodulin-dependent kinases regulate a number of different stress responses, including response to mating pheromone, response to organic acids, and tolerance to heat stress (7).

Other roles of Calmodulin

Calmodulin plays additional roles in the cell, and it is not yet clear whether these processes are dependent on or independent of calcium. Calmodulin plays a role in vacuole fusion. Some calmodulin mutants display abnormal vacuolar morphologies, calmodulin binds to vacuoles in a Ca2+-dependent manner, and in vitro assays indicate that calmodulin is required for a post-docking step in vacuole fusion (6). However, it is not clear whether this process requires calcium as a non-calcium binding mutant shows normal vacuolar morphology in vivo (7) and variable results have been obtained in assays testing whether the non-calcium binding mutant protein supports vacuolar fusion in vitro (9). The effect of calmodulin on vacuolar fusion may be due to its affects on remodelling of the actin cytoskeleton (19). Overexpression of Mss4p, a phosphatidylinositol-4-phosphate 5-kinase involved in the organization of the actin cytoskeleton, suppresses the actin cytoskeleton defects of a particular calmodulin mutation, which also causes reduced levels of phosphatidylinositol (4,5)-bisphosphate (8).

Structure of calmodulin and comparison with those from other organims

Calmodulin is a highly conserved protein found in all eukaryotes, including animals, plants, and fungi. While the amino acid sequences of calmodulins from multicellular organisms are more than 90% identical, that from S. cerevisiae is significantly diverged, with only 60% identity to vertebrate calmodulins. Calmodulin contains four EF-hand domains; in most species, including S. pombe, each motif chelates one Ca2+ ion. However, in calmodulin from S. cerevisiae, the fourth motif is divergent and does not bind calcium, making it the only yet characterized calmodulin to bind less than four Ca2+ ions. Despite these structural differences between calmodulin of S. cerevisiae and other organisms, its basic functions appear to be conserved (7).

Last updated: 2007-07-24