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Biomedical subjects

Wilson K Clements

Publications and source records attributed to Wilson K Clements.

5 recordsLinked to original sources
PubMed2005

LZIC regulates neuronal survival during zebrafish development.

Development of the brain and central nervous system is a complex process involving localized gene expression and regulated cell death and proliferation. Here, we describe a gene involved in neuronal survival, the zebrafish ortholog of the human lzic gene. Zebrafish lzic is expressed ubiquitously during early development and later becomes enriched in the developing brain. Using antisense morpholino oligonucleotides, we demonstrate that zebrafish lzic is required zygotically for the survival of distinct neuronal populations. LZIC is closely related to ICAT, a physiological inhibitor of the Wnt pathway that interacts physically and functionally with beta-catenin to prevent the transcription of Wnt target genes. LZIC's ICAT-homologous region is highly similar to ICAT with particular conservation of residues that are used by ICAT for beta-catenin-binding. Surprisingly, despite this high similarity, LZIC does not interact with beta-catenin in vitro or in vivo. Our results reveal that LZIC, a protein conserved in vertebrates, is required for neuronal survival in zebrafish.

Amino Acid Sequence↗
PubMed2004

Crystal structure of a beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function.

The tumor suppressor adenomatous polyposis coli (APC) plays a critical role in the turnover of cytosolic beta-catenin, the key effector of the canonical Wnt signaling pathway. APC contains seven 20 amino acid (20 aa) beta-catenin binding repeats that are required for beta-catenin turnover. We have determined the crystal structure of beta-catenin in complex with a phosphorylated APC fragment containing two 20 aa repeats. Surprisingly, one single phosphorylated 20 aa repeat, together with its flanking regions, covers the entire structural groove of beta-catenin and may thus compete for beta-catenin binding with all other beta-catenin armadillo repeat partners. Our biochemical studies show that phosphorylation of the APC 20 aa repeats increases the affinity of the repeats for beta-catenin by 300- to 500-fold and the phosphorylated 20 aa repeats prevent beta-catenin binding to Tcf. Our work suggests that the phosphorylation of the APC 20 aa repeats could be a critical switch for APC function.

Adenomatous Polyposis Coli Protein↗
PubMed2003

Crystal structure of a beta-catenin/axin complex suggests a mechanism for the beta-catenin destruction complex.

The "beta-catenin destruction complex" is central to canonical Wnt/beta-catenin signaling. The scaffolding protein Axin and the tumor suppressor adenomatous polyposis coli protein (APC) are critical components of this complex, required for rapid beta-catenin turnover. We determined the crystal structure of a complex between beta-catenin and the beta-catenin-binding domain of Axin (Axin-CBD). The Axin-CBD forms a helix that occupies the groove formed by the third and fourth armadillo repeats of beta-catenin and thus precludes the simultaneous binding of other beta-catenin partners in this region. Our biochemical studies demonstrate that, when phosphorylated, the 20-amino acid repeat region of APC competes with Axin for binding to beta-catenin. We propose that a key function of APC in the beta-catenin destruction complex is to remove phosphorylated beta-catenin product from the active site.

Adenomatous Polyposis Coli Protein↗
PubMed2002

The crystal structure of the beta-catenin/ICAT complex reveals the inhibitory mechanism of ICAT.

Beta-catenin is a multifunctional protein involved in both cell adhesion and transcriptional activation. Transcription mediated by the beta-catenin/Tcf complex is involved in embryological development and is upregulated in various cancers. We have determined the crystal structure at 2.5 A resolution of a complex between beta-catenin and ICAT, a protein that prevents the interaction between beta-catenin and Tcf/Lef family transcription factors. ICAT contains a 3-helix bundle that binds armadillo repeats 10-12 and a C-terminal tail that, similar to Tcf and E-cadherin, binds in the groove formed by armadillo repeats 5-9 of beta-catenin. We show that ICAT selectively inhibits beta-catenin/Tcf binding in vivo, without disrupting beta-catenin/cadherin interactions. Thus, it should be possible to design cancer therapeutics that inhibit beta-catenin-mediated transcriptional activation without interfering with cell adhesion.

Adaptor Proteins, Signal Transducing↗