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1.A.81 The Low Affinity Ca2+ Channel (LACC) Family

During the mating process of yeast cells, two Ca2+ influx pathways become activated. The resulting elevation of cytosolic free Ca2+ activates downstream signaling factors that promote long term survival of unmated cells. The high affinity Ca2+ influx system is composed of Cch1p and Mid1p (TC# 1.A.1.11.10) and is sensitive to feedback inhibition by calcineurin, a Ca2+/calmodulin-dependent protein phosphatase. The low affinity Ca2+ influx system (LACS) genes that when deleted lead to defects in LACS activity but not high affinity Ca2+ influx system activity are pheromone-responsive. Several factors implicated in polarized morphogenesis and cell fusion (Fus1p, Fus2p, Rvs161p, Bni1p, Spa2p, and Pea2p) were found to be necessary for LACS activity. Each of these factors was also required for activation of the cell integrity mitogen-activated protein kinase cascade during the response to alpha-factor. A polytopic plasma membrane protein, Fig1p, was required for LACS activity but not required for activation of Mpk1p mitogen-activated protein kinase. Mpk1p was not required for LACS activity, suggesting Mpk1p and Fig1p define two independent branches in the pheromone response pathways. Fig1p-deficient mutants exhibit defects in the cell-cell fusion step of mating, but unlike fus1 and fus2 mutants, the fusion defect of fig1 mutants can be largely suppressed by high Ca2+ conditions, which bypass the requirement for LACS. Fig1p may therefore be the low affinity Ca2+ channel, providing Ca2+ signals in the cell fusion step of mating (Muller et al., 2003).

C. albicans FIG1 (Ca2+-channel) is a mating-induced gene encoding a putative 4-transmembrane domain protein that shares sequence similarities with members of the SUR7 claudin superfamily. In Saccharomyces cerevisiae, Fig1 is required for shmoo fusion and is upregulated in response to mating pheromones. Expression of CaFIG1 was also strongly activated in the presence of cells of the opposite mating type. CaFig1-green fluorescent protein (GFP) was visible only during the mating response, when it localized predominantly to the plasma membrane and perinuclear zone in mating projections and daughter cells. At the plasma membrane, CaFig1-GFP was visualized as discontinuous zones, but the distribution of perinuclear CaFig1-GFP was homogeneous. Exposure to pheromone induced a 5-fold increase in Ca2+ uptake in mating-competent opaque cells. Uptake was reduced substantially in the fig1Δ null mutant. CaFig1 is therefore involved in Ca2+influx and localizes to membranes that are destined to undergo fusion during mating (Yang et al., 2011).

LACC homologues are found in numerous fungal species. Most are of similar size (~240-300 residues) and have 4 TMSs in a 1 3 arrangement. The reaction believed to be catalyzed by Fig1p is:

Ca2+ (out) ⇌ Ca2+ (in)

References associated with 1.A.81 family:

Cavinder, B. and F. Trail. (2012). Role of Fig1, a component of the low-affinity calcium uptake system, in growth and sexual development of filamentous fungi. Eukaryot. Cell. 11: 978-988. 22635922
Muller, E.M., N.A. Mackin, S.E. Erdman, and K.W. Cunningham. (2003). Fig1p facilitates Ca2+ influx and cell fusion during mating of Saccharomyces cerevisiae. J. Biol. Chem. 278: 38461-38469. 12878605
Palma-Guerrero J., Zhao J., Goncalves AP., Starr TL. and Glass NL. (2015). Identification and characterization of LFD-2, a predicted fringe protein required for membrane integrity during cell fusion in neurospora crassa. Eukaryot Cell. 14(3):265-77. 25595444
Yang, M., A. Brand, T. Srikantha, K.J. Daniels, D.R. Soll, and N.A. Gow. (2011). Fig1 facilitates calcium influx and localizes to membranes destined to undergo fusion during mating in Candida albicans. Eukaryot. Cell. 10: 435-444. 21216943