Abstract
Slac2-a/Melanophilin Contains Multiple PEST-like Sequences That Are Highly Sensitive to Proteolysis
Highlights
Cytes, because defects in this step cause pigment dilution in the skin and hair in human diseases (e.g. Griscelli syndrome) and the corresponding coat-color mutant mice [1, 3,4,5,6,7,8]
We and others had previously shown that formation of a tripartite protein complex composed of Rab27A, synaptotagmin-like protein homologue lacking C2 domains-a (Slac2-a), and myosin Va is indispensable for normal melanosome transport in melanocytes in vivo [10, 11, 17, 18]
We discovered that the C-terminal domain of Slac2-a contains multiple PEST-like sequences (Fig. 2), and we have presented several lines of evidence that these sequences are highly sensitive to proteases in vitro and in intact melanocytes
Summary
Cytes, because defects in this step cause pigment dilution in the skin and hair in human diseases (e.g. Griscelli syndrome) and the corresponding coat-color mutant mice (e.g. dilute, ashen, and leaden) [1, 3,4,5,6,7,8]. The results of recent genetic analyses of these mutant animals and biochemical studies of their gene products have indicated that a tripartite protein complex formed by myosin Va (dilute gene product), Slac2-a/melanophilin (GS3/leaden gene product), and Rab27A (ashen gene product) is essential for melanosome transfer from the perinuclear region of melanocytes to their actin-rich cell periphery Slac2-a functions as a linker protein between myosin Va and Rab27A and directly and simultaneously binds the GTP-bound form of Rab27A on the melanosome via the N-terminal synaptotagmin-like protein (Slp) homology domain (referred to as SHD or RBD27 (Rab binding domain specific for Rab isoforms)) (9 –11, 14, 17, 21–26) and myosin Va, an actin-based motor protein, via the large C-terminal domain (9 –11, 14, 17, 18, 27). Together with the fact that yeast Vac17p, a linker protein of the yeast class V myosin Myo2p contains a functional PEST sequence [35, 36], we discuss the convergent evolution of the cargo receptor for class V myosins in membrane trafficking
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