In 2012, Nookala et al., (2012) described the structure of the C-terminal domain of FLCN, determined by X-ray crystallography (PDB ID: 3V42). Residues 341-579 of FLCN were found to form a β-sheet with helices packed on one side, followed by an all helical region. This fold is remarkably similar to that of DENN-domain proteins, which function as Rab guanine nucleotide exchange factors (GEFs). As such, Nookala et al., (2012) proposed that FLCN may function as a Rab GEF, and thus play a role in membrane trafficking.
Residues 104 – 266 of FLCN are predicted to form a domain similar to that in found yeast which is required for Golgi to plasma membrane transport (PFAM ID: PF11704). Interestingly the majority of this region falls within the region that Nahorski et al. (2011) found to be highly evolutionarily conserved and is in a region of homology with the S. pombe homologue of FLCN, BHD1 (see alignment in Section 6) (van Slegtenhorst et al., 2007).
Nookala et al. (2012) also analysed the N-terminal domain of FLCN using secondary structure prediction programmes. The domain is predicted to form a longin domain, which is present in other DENN-domain containing proteins and found in proteins involved in membrane trafficking. Work is currently underway to determine the structure of this region of FLCN. The N-terminal 85 amino acids are predicted to form a metal-ion-binding module. The N- and C-terminal domains of FLCN are connected by a 40 amino acid disordered linker region. This region contains a bipartite tryptophan (WD-WQ) motif, which has been shown to be a binding motif for kinesin light chain 1, which is an intracellular trafficking protein (Dodding et al., 2011).