At ERES, ALG-2 works with another penta-EF hand protein, PEF1, to regulate CU元 and KLHL12-dependent ubiquitylation of COPII ( 7). ALG-2 also mediate effects of Ca 2+ released by TRPML1 at lysosomes ( 6). In the Endosomal Sorting Complex Required for Transport (ESCRT) pathway ( 2, 3), ALG-2 senses Ca 2+ released into the cytosol by plasma ( 4) and lysosome membrane damage ( 5), triggering recruitment of repair factors. These data thus reveal the nature of direct Ca 2+-dependent membrane binding and its interplay with Ca 2+-dependent protein binding in the cellular functions of ALG-2.Īpoptosis-linked gene (ALG-2) plays a central role in regulating various cellular processes, including plasma membrane and lysosome repair and vesicle budding at ER exit sites (ERES) ( 1). In vitro reconstitution shows that the ALG-2 membrane-binding defect can be rescued by binding to ESCRT-I. ALG-2 membrane binding mutants have reduced or abrogated ERES localization in response to Thapsigargin-induced Ca 2+ release but still localize to lysosomes following lysosomal Ca 2+ release. By combining GUV-based experiments and molecular dynamics simulations, we show that charge-reversed mutants of ALG-2 at these locations disrupt membrane recruitment. ALG-2 also binds directly to acidic membranes in the presence of Ca 2+ by a combination of electrostatic and hydrophobic interactions. In the presence of Ca 2+, ALG-2 binds to ESCRT-I and ALIX in membrane repair and to SEC31A at ERES. ALG-2 functions in the repair of damage to both the plasma and lysosome membranes and in COPII-dependent budding at endoplasmic reticulum exit sites (ERES). Apoptosis Linked Gene-2 (ALG-2) is a multifunctional intracellular Ca 2+ sensor and the archetypal member of the penta-EF hand protein family.
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