Meta-Biol

• Pathways

RAB32 and RAB38 play non-redundant but overlapping roles in melanosome and lysosome-related organelle (LRO) biogenesis (Loftus et al, 2002; Wasmeier et al, 2006; Lopes et al, 2007; Wang et al, 2008; Bultema et al, 2012; reviewed in Bultema and di Pietro, 2012). Through interaction with effector protein ANKRD27 (also known as VARP, a RAB21-specific GEF), RAB32 and RAB38 control trafficking of melanogenic enzymes; ANKRD27 GEF activity does not appear to be essential for this, however (Tamura et al, 2009; Tamura et al, 2011; Ohbayahsi et al, 2012). BLOC-3, a dimeric complex of HPS1 and HPS4, has RAB32- and RAB38 GEF activity and mutation in the genes encoding HPS1 and HPS4 results in defects in pigmentation and mislocalization of RAB32 and 38, and are associated with the rare autosomal recessive disorder Hermansky-Pudlak Syndrome (Gerondopoulos et al, 2012; reviewed in Ishida et al, 2016). Interaction of RAB32:GDP or RAB38:GDP with BLOC-3 promotes release of GDP, allowing GTP to bind, and precludes the interaction of the RAB proteins with GDI and CHM proteins.