Characterizing the Importance of the CO1 SLiM in Regulating Kekkon 5 Activity

Miller, Manon C.

Student Work

Characterizing the Importance of the CO1 SLiM in Regulating Kekkon 5 Activity

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Kekkon 5 (Kek5) is a regulator of BMP and TGF-β signaling in Drosophila, pathways well conserved and known for their role in development and disease. Kek5 is a member of a family of transmembrane molecules, defined as LIGs due to the presence of leucine-rich repeats (LRR) and Immunoglobulin (Ig) domains in their extracellular domains, but with no known catalytic activities in their intracellular domains. Phylogenetic analysis has identified a number of conserved motifs, or SLiMs (short, linear, interspersed motifs), of unknown function within the intracellular domain Kek5. One of these SLiMs, CO1, is highly conserved across the Kekkon family of LIGs and may act to regulate Kek5 activity. The sequence of CO1 is related to the P1 binding domain of the Drosophila axon guidance receptor Frazzled and its human ortholog Deleted in Colorectal Cancer (DCC), which has been implicated in regulating their activity and interactions with a co-receptor, Unc-5. To address the role of CO1 in Kek5 function the specific CO1 SLiM sequence in Kek5 was defined through a phylogenetic analysis and three variants of the protein were designed, a CO1 deletion and two versions in which the CO1 sequence was replaced with the Kek6 and Frazzled CO1. Two of the constructs have been generated and confirmed. These variants are currently being assessed in both in vivo and in vitro assays to determine their effect on Kek5 activity.

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