Hermansky-Pudlak syndrome (HPS) is a disorder of organelle biogenesis in which oculocutaneous albinism, bleeding and pulmonary fibrosis result from defects of melanosomes, platelet dense granules and lysosomes []. HPS is common in Puerto Rico, where is mostly caused by mutations in the genes HPS1 or HPS3. Another HPS locus, HPS4 was identified by using mouse models []. It was suggested that HPS4 and HPS1 proteins may function in the same pathway of organelle biogenesis [].This family represents BLOC-3 complex member HPS4, a component of the BLOC-3 complex, a complex that acts as a guanine exchange factor (GEF) for RAB32 and RAB38, promotes the exchange of GDP to GTP, converting them from an inactive GDP-bound form into an active GTP-bound form. The BLOC-3 complex plays an important role in the control of melanin production and melanosome biogenesis and promotes the membrane localization of RAB32 and RAB38 [].
Longin domains are evolutionarily conserved regions widely distributed among eukaryotes, involved in membrane dynamic regulation and exhibit similarities in primary sequence and secondary structure. Longin-like domains are found in FUZ and related proteins, such as the MON1 and HPS1 proteins [, , ]. The MON1/CCZ1 complex (MC1) is the GDP/GTP exchange factor (GEF) for the Rab GTPase Ypt7/Rab7 during vesicular trafficking []. The HPS1/HPS4 complex (BLOC-3) is a Rab32 and Rab38 GEF and is required for biogenesis of melanosomes and platelet dense granules []. Inturned (INTU) and Fuzzy (FUZ) proteins interact as members of the ciliogenesis and planar polarity effector (CPLANE) complex that controls recruitment of intraflagellar transport machinery to the basal body of primary cilia [, ]. Structurally, these domains are composed of an alpha/beta fold which contains five anti-parallel β-strands organised as a central β-sheet and around it, two α-helices [].This entry represents the third Longin domain found in CCZ1, INTU and HPS4 proteins.
