Hexa-Longin domain scaffolds for inter-Rab signalling

Abstract

CPLANE is a protein complex required for assembly and maintenance of primary cilia. It contains several proteins, such as INTU, FUZ, WDPCP, JBTS17 and RSG1 (REM2-and RAB-like small GTPase 1), whose genes are mutated in ciliopathies. Using two contrasting evolutionary analyses, coevolution-based contact prediction and sequence conservation, we first identified the INTU/FUZ heterodimer as a novel member of homologous HerMon (Hermansky-Pudlak syndrome and MON1-CCZ1) complexes. Subsequently, we identified homologous Longin domains that are triplicated in each of these six proteins (MON1A, CCZ1, HPS1, HPS4, INTU and FUZ). HerMon complexes are known to be Rab effectors and Rab GEFs (Guanine nucleotide Exchange Factors) that regulate vesicular trafficking. Consequently, INTU/FUZ, their homologous complex, is likely to act as a GEF during activation of Rab GTPases involved in ciliogenesis.