Abstract
SummaryCPLANE 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. Supplementary information Supplementary data are available at Bioinformatics online.
Highlights
Many diverse cell processes are regulated by small GTPases, switching between active (GTP-bound) and inactive (GDP-bound) states
2.1 A new Longin domain in INTU We initiated our analyses with a JackHMMER iterative search (Finn et al, 2015) of the UniRef50 database (The UniProt Consortium, 2019) using the human INTU protein sequence as query
The predicted secondary structure (Jones, 2017) of this INTU conserved region was consistent with known Longin domain structures (Supplementary Fig. S1)
Summary
Many diverse cell processes are regulated by small GTPases, switching between active (GTP-bound) and inactive (GDP-bound) states. Multiple small GTPases of the Rab family, and their GEFs, for example, are critical for the assembly of cilia (ciliogenesis) and can be mutated in ciliopathies (Blacque et al, 2018). Mouse mutants for genes encoding the Rab-like small GTPase RSG1 or ciliopathy-associated proteins Fuzzy (FUZ) and Inturned (INTU) show developmental abnormalities characteristic of decreased cilia-dependent Hedgehog signalling (Agbu et al, 2018; Gray et al, 2009; Zeng et al, 2010). These three proteins interact as members of the ciliogenesis and planar polarity effector (CPLANE) complex that controls recruitment of intraflagellar transport machinery to the basal body (Toriyama et al, 2016). To investigate the evolutionary provenance of the INTU protein family, we embarked on a deep sequence analysis taking advantage of both protein sequence conservation and coevolution-based contact prediction approaches
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