F-box protein substrate recognition

Ubiquitin E3 ligases represent an increasingly diverse group of proteins whose precise biologic role still remains enigmatic. Of the SCF (Skp1-Cullin1-F-box) E3 ligase family, for example, only very few subunits from over 60 family members are well-characterized. The SCF apparatus contains a multi-subunit catalytic core consisting of Skp1, Cullin1 and the E2 ubiquitin-conjugating (Ubc) enzyme and an F box receptor-like component that targets many substrates. The F-box proteins have two functional domains: an NH 2 terminal F-box motif that binds Skp1, and a C-terminal leucine-rich repeat (LRR), WD motif or another signature that recognizes substrates. SCF ligase complexes are critically involved in regulating DNA repair, cell cycle progression, inflammation, centrosome stability, mitotic fidelity and cellular proliferation. Hence, it is not surprising that novel targeted therapies might involve modulating activities of SCF subunits in cells during neoplasia, cell growth and repair or inflammation. Following its initial description, F-box protein Fbxl2 was shown to interact with hepatitis C virus. However, until recently, the authentication of Fbxl2 as a ubiquitin E3 ligase component and its molecular behavior was not demonstrated. Recent studies show that Fbxl2 acts as the receptor component of a classical SCF ubiquitin E3 ligase, recognizing a calmodulin (CaM)-binding signature. CaM is a highly conserved protein that binds to its targets in a calcium-dependent or calcium-independent manner by recognizing specific molecular signatures including an IQ motif (I/LQXXXRGXXXR), a 1-10 or 1-5-10-binding motif. Indeed, recognition of an IQ motif by Fbxl2 represents an unusual F-box protein substrate recognition A new insight